3-phenyl-pyrazole derivatives as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto

ABSTRACT

The present invention relates to certain 3-phenyl-pyrazole derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the 5-HT 2A  serotonin receptor. 
     
       
         
         
             
             
         
       
     
     Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of platelet aggreagation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, reducing the risk of blood clot formation, asthma or symptoms thereof, agitation or a symptom, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette&#39;s syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like. 
     The present invention also relates to the methods for the treatment of 5-HT 2A  serotonin receptor mediated disorders in combination with other pharmaceutical agents administered separately or together.

FIELD OF THE INVENTION

The present invention relates to certain 3-phenyl-pyrazole derivativesof Formula (Ia) and pharmaceutical compositions thereof that modulatethe activity of the 5-HT_(2A) serotonin receptor. Compounds andpharmaceutical compositions thereof are directed to methods useful inthe treatment of platelet aggregation, coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, atrialfibrillation, reducing the risk of blood clot formation, asthma orsymptoms thereof, agitation or a symptom thereof, behavioral disorders,drug induced psychosis, excitative psychosis, Gilles de la Tourette'ssyndrome, manic disorder, organic or NOS psychosis, psychotic disorder,psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophreniaand related disorders, sleep disorders, diabetic-related disorders,progressive multifocal leukoencephalopathy and the like.

The present invention also relates to the methods for the treatment of5-HT_(2A) serotonin receptor mediated disorders in combination withother pharmaceutical agents administered separately or together.

BACKGROUND OF THE INVENTION G Protein Coupled Receptors

G Protein coupled receptors share a common structural motif. All thesereceptors have seven sequences of between 22 to 24 hydrophobic aminoacids that form seven alpha helices, each of which spans the membrane.The transmembrane helices are joined by strands of amino acids having alarger loop between the fourth and fifth transmembrane helix on theextracellular side of the membrane. Another larger loop, composedprimarily of hydrophilic amino acids, joins transmembrane helices fiveand six on the intracellular side of the membrane. The carboxy terminusof the receptor lies intracellularly with the amino terminus in theextracellular space. It is thought that the loop joining helices fiveand six, as well as, the carboxy terminus, interact with the G protein.Currently, Gq, Gs, Gi and Go are G proteins that have been identified.

Under physiological conditions, G protein coupled receptors exist in thecell membrane in equilibrium between two different states orconformations: an “inactive” state and an “active” state. A receptor inan inactive state is unable to link to the intracellular transductionpathway to produce a biological response. Changing the receptorconformation to the active state allows linkage to the transductionpathway and produces a biological response.

A receptor may be stabilized in an active state by an endogenous ligandor an exogenous agonist ligand. Recent discoveries such as, includingbut not exclusively limited to, modifications to the amino acid sequenceof the receptor provide means other than ligands to stabilize the activestate conformation. These means effectively stabilize the receptor in anactive state by simulating the effect of a ligand binding to thereceptor. Stabilization by such ligand-independent means is termed“constitutive receptor activation.”

Serotonin Receptors

Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an importantclass of G protein coupled receptors. Serotonin is thought to play arole in processes related to learning and memory, sleep,thermoregulation, mood, motor activity, pain, sexual and aggressivebehaviors, appetite, neurodegenerative regulation, and biologicalrhythms. Not surprisingly, serotonin is linked to pathophysiologicalconditions such as anxiety, depression, obsessive compulsive disorders,schizophrenia, suicide, autism, migraine, emesis, alcoholism, andneurodegenerative disorders. With respect to anti-psychotic treatmentapproaches focused on the serotonin receptors, these types oftherapeutics can generally be divided into two classes, the “typical”and the “atypical.” Both have anti-psychotic effects, but the typicalsalso include concomitant motor-related side effects (extra pyramidalsyndromes, e.g., lip-smacking, tongue darting, locomotor movement, etc).Such side effects are thought to be associated with the compoundsinteracting with other receptors, such as the human dopamine D₂ receptorin the nigro-striatal pathway. Therefore, an atypical treatment ispreferred. Haloperidol is considered a typical anti-psychotic, andclozapine is considered an atypical anti-psychotic.

Serotonin receptors are divided into seven subfamilies, referred to as5-HT₁ through 5-HT₇, inclusive. These subfamilies are further dividedinto subtypes. For example, the 5-HT₂ subfamily is divided into threereceptor subtypes: 5-HT_(2A), 5-HT_(2B), and 5-HT_(2C). The human5-HT_(2C) receptor was first isolated and cloned in 1987, and the human5-HT_(2A) receptor was first isolated and cloned in 1990. These tworeceptors are thought to be the site of action of hallucinogenic drugs.Additionally, antagonists to the 5-HT_(2A) and 5-HT_(2C) receptors arebelieved to be useful in treating depression, anxiety, psychosis, andeating disorders.

U.S. Pat. No. 4,985,352 describes the isolation, characterization, andexpression of a functional cDNA clone encoding the entire human5-HT_(1C) receptor (now known as the 5-HT_(2C) receptor). U.S. Pat. Nos.5,661,024 and 6,541,209 describe the isolation, characterization, andexpression of a functional cDNA clone encoding the entire human5-HT_(2A) receptor.

Mutations of the endogenous forms of the rat 5-HT_(2A) and rat 5-HT_(2C)receptors have been reported to lead to constitutive activation of thesereceptors (5-HT_(2A): Casey, C. et al. (1996) Society for NeuroscienceAbstracts, 22:699.10, hereinafter “Casey”; 5-HT_(2C): Herrick-Davis, K.,and Teitler, M. (1996) Society for Neuroscience Abstracts, 22:699.18,hereinafter “Herrick-Davis 1”; and Herrick-Davis, K. et al. (1997) J.Neurochemistry 69(3): 1138, hereinafter “Herrick-Davis-2”). Caseydescribes a mutation of the cysteine residue at position 322 of the rat5-HT_(2A) receptor to lysine (C322K), glutamine (C322Q), and arginine(C322R) which reportedly led to constitutive activation. Herrick-Davis 1and Herrick-Davis 2 describe mutations of the serine residue at position312 of the rat 5-HT_(2C) receptor to phenylalanine (S312F) and lysine(S312K), which reportedly led to constitutive activation.

SUMMARY OF THE INVENTION

One aspect of the present invention encompasses certain3-phenyl-pyrazole derivatives as shown in Formula (Ia):

or a pharmaceutically acceptable salt, hydrate or solvate thereof;

wherein:

V is O, S, S(═O), S(═O)₂ or NR₁₀;

W is C₁₋₄ alkylene optionally substituted with 1 to 8 substituentsselected independently from the group consisting of C₁₋₃ alkyl, C₁₋₄alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, halogen and oxo; or W is absent;

X is C(═O), C(═S) or absent;

Y is O, NR₁₁ or absent;

Z is C₁₋₄ alkylene, or C₃₋₆ cycloalkylene, each optionally substitutedwith 1 to 8 substituents selected independently from the groupconsisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl,halogen, hydroxyl, and oxo; or Z is absent;

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₃₋₇ cycloalkyl;

R₂ is selected from the group consisting of H, C₁₋₆ acyl, C₁₋₆ acyloxy,C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₂₋₈ dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen,C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, thiol, nitro andsulfonamide;

R₃ is selected from the group consisting of H, C₂₋₆ alkenyl, C₁₋₆ alkyl,C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each ofsaid C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₃₋₇cycloalkyl, heteroaryl and phenyl groups are optionally substituted with1 to 5 substituents selected independently from the group consisting ofC₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₆alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, nitro and sulfonamide;

R₄ is heterobicyclic, heterocyclic, or heteroaryl each optionallysubstituted with substituents selected independently from the groupconsisting of C₁₋₆ acyl, C₁₋₁₂ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₆alkoxycarbonylamino, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,C₃₋₇ cycloalkylcarbonyl, C₂₋₆ dialkylcarboxamide, formyl, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heteroaryl, hydroxyl, nitro,phenyl and sulfonamide; wherein said C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, amino, carbo-C₁₋₆-alkoxy, andheteroaryl are each optionally substituted with substituents selectedindependently from the group consisting of C₁₋₆ alkyl, C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, andphenyl;

R₅, R₆, and R₇ are each selected independently from the group consistingof H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkylimino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆haloalkylthio, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenyl;

R₈ is C₁₋₈ alkyl, C₂₋₆ alkenyl, aryl, C₃₋₇ cycloalkyl, or heteroaryleach optionally substituted with substituents selected independentlyfrom the group consisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,C₁₋₆ alkylimino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₂₋₈ dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen,C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, heterocyclic, hydroxyl, thiol,nitro, phenoxy and phenyl, or two adjacent substituents together withsaid aryl or said heteroaryl form a C₅₋₇ cycloalkyl optionallycomprising 1 to 2 oxygen atoms and optionally substituted with F, Cl orBr; and wherein said C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆alkylamino, C₁₋₆ alkylimino, C₂₋₈ dialkylamino, heterocyclic, and phenylare each optionally substituted with 1 to 5 substituents selectedindependently from the group consisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl,C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl,thiol and nitro; and

R₉, R₁₀, and R₁₁ are each independently H or C₁₋₈ alkyl;

provided that the compound is other thanN-[4-oxiranylmethoxy-3-(2H-pyrazol-3-yl)-phenyl]-acetamide.

One aspect of the present invention encompasses pharmaceuticalcompositions comprising a compound of the present invention and apharmaceutically acceptable carrier.

One aspect of the present invention encompasses methods for modulatingthe activity of a 5-HT_(2A) serotonin receptor by contacting thereceptor with a compound according to any of the embodiments describedherein or a pharmaceutical composition thereof.

One aspect of the present invention encompasses methods for treating a5-HT_(2A) mediated disorder in an individual comprising administering tosaid individual in need thereof a therapeutically effective amount of acompound according to any of the embodiments described herein or apharmaceutical composition thereof.

One aspect of the present invention encompasses methods for treatingplatelet aggregation in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound according to any of the embodiments described herein or apharmaceutical composition thereof. It is understood that treatment ofplatelet aggregation refers to any reduction of platelet aggregationthat results in an amelioration of a pathophysiological conditionassociated with platelet aggregation.

One aspect of the present invention encompasses methods for treating oneor more conditions associated with platelet aggregation in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition thereof.

One aspect of the present invention encompasses methods for treating a5-HT_(2A) mediated disorder selected from the group consisting ofcoronary artery disease, myocardial infarction, transient ischemicattack, angina, stroke, and atrial fibrillation in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition thereof.

One aspect of the present invention encompasses methods for reducing therisk of blood clot formation in an angioplasty or coronary bypasssurgery individual comprising administering to the individual in needthereof a therapeutically effective amount of a compound according toany of the embodiments described herein or a pharmaceutical compositionthereof.

One aspect of the present invention encompasses methods for reducing therisk of blood clot formation in an individual suffering from atrialfibrillation, comprising administering to the individual in need thereofa therapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition thereof.

One aspect of the present invention encompasses methods for treatingasthma in an individual comprising administering to the individual inneed thereof a therapeutically effective amount of a compound accordingto any of the embodiments described herein or a pharmaceuticalcomposition thereof.

One aspect of the present invention encompasses methods for treating asymptom of asthma in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound according to any of the embodiments described herein or apharmaceutical composition thereof.

One aspect of the present invention encompasses methods for treatingagitation or a symptom thereof in an individual comprising administeringto the individual in need thereof a therapeutically effective amount ofa compound according to any of the embodiments described herein or apharmaceutical composition thereof. In some embodiments, the individualis a cognitively intact elderly individual.

One aspect of the present invention encompasses methods for treatingagitation or a symptom thereof in an individual suffering from dementiacomprising administering to the individual in need thereof atherapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition thereof. Insome embodiments, the dementia is due to a degenerative disease of thenervous system. In some embodiments, the dementia is Alzheimers disease,Lewy Body, Parkinson's disease or Huntington's disease. In someembodiments, the dementia is due to diseases that affect blood vessels.In some embodiments, the dementia is due to stroke or multi-infarctdementia.

One aspect of the present invention encompasses methods for treating anindividual suffering from at least one of the indications selected fromthe group consisting of behavioral disorder, drug induced psychosis,excitative psychosis, Gilles de la Tourette's syndrome, manic disorder,organic or NOS psychosis, psychotic disorder, psychosis, acuteschizophrenia, chronic schizophrenia and NOS schizophrenia comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a therapeutically effective amount of a dopamine D₂receptor antagonist and a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition thereof. In someembodiments, the dopamine D₂ receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods for treating anindividual with infantile autism, Huntington's chorea or nausea andvomiting from chemotherapy or chemotherapeutic antibodies comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a dopamine D₂ receptor antagonist and a compoundaccording to any of the embodiments described herein or a pharmaceuticalcomposition thereof. In some embodiments, the dopamine D₂ receptorantagonist is haloperidol.

One aspect of the present invention encompasses methods for treatingschizophrenia in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of adopamine D₂ receptor antagonist and a compound according to any of theembodiments described herein or a pharmaceutical composition thereof. Insome embodiments, the dopamine D₂ receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods for treatingnegative symptoms of schizophrenia induced by the administration ofhaloperidol to an individual suffering from schizophrenia, comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition thereof. In someembodiments, the dopamine D₂ receptor antagonist or haloperidol and thecompound or pharmaceutical composition are administered in separatedosage forms. In some embodiments, the dopamine D₂ receptor antagonistor haloperidol and the compound or pharmaceutical composition areadministered in a single dosage form.

One aspect of the present invention encompasses methods for treating asleep disorder in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound according to any of the embodiments described herein or apharmaceutical composition thereof. In some embodiments, the sleepdisorder is a dyssomnia. In some embodiments, the dyssomnia is selectedfrom the group consisting of psychophysiological insomnia, sleep statemisperception, idiopathic insomnia, obstructive sleep apnea syndrome,central sleep apnea syndrome, central alveolar hypoventilation syndrome,periodic limb movement disorder, restless leg syndrome, inadequate sleephygiene, environmental sleep disorder, altitude insomnia, adjustmentsleep disorder, insufficient sleep syndrome, limit-setting sleepdisorder, sleep-onset association disorder, nocturnal eating or drinkingsyndrome, hypnotic dependent sleep disorder, stimulant-dependent sleepdisorder, alcohol-dependent sleep disorder, toxin-induced sleepdisorder, time zone change (jet lag) syndrome, shift work sleepdisorder, irregular sleep-wake pattern, delayed sleep phase syndrome,advanced sleep phase syndrome and non-24-hour sleep-wake disorder. Insome embodiments, the sleep disorder is a parasomnia. In someembodiments, the parasomnia is selected from the group consisting ofconfusional arousals, sleepwalking and sleep terrors, rhythmic movementdisorder, sleep starts, sleep talking and nocturnal leg cramps. In someembodiments, the sleep disorder is associated with a medical orpsychiatric disorder. In some embodiments, the medical or psychiatricdisorder is selected from the group consisting of psychoses, mooddisorders, anxiety disorders, panic disorders, alcoholism, cerebraldegenerative disorders, dementia, parkinsonism, fatal familial insomnia,sleep-related epilepsy, electrical status epilepticus of sleep,sleep-related headaches, sleeping sickness, nocturnal cardiac ischemia,chronic obstructive pulmonary disease, sleep-related asthma,sleep-related gastroesophageal reflux, peptic ulcer disease, fibrositissyndrome, osteoarthritis, rheumatoid arthritis, fibromyalgia andpost-surgical sleep disorder.

One aspect of the present invention encompasses methods for treating adiabetic-related disorder in an individual comprising administering tothe individual in need thereof a therapeutically effective amount of acompound according to any of the embodiments described herein or apharmaceutical composition thereof. In some embodiments, thediabetic-related disorder is diabetic peripheral neuropathy. In someembodiments, the diabetic-related disorder is diabetic nephropathy. Insome embodiments, the diabetic-related disorder is diabetic retinopathy.

One aspect of the present invention encompasses methods for treatingprogressive multifocal leukoencephalopathy in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition thereof. In someembodiments, the individual in need thereof has a lymphoproliferativedisorder. In some embodiments, the individual in need thereof hascarcinomatosis. In some embodiments, the individual in need thereof isimmunocompromised. In some embodiments, the individual in need thereofis infected with HIV. In some embodiments, the HIV-infected individualhas a CD4+ cell count of ≦200/mm³. In some embodiments, the HIV-infectedindividual has AIDS. In some embodiments, the HIV-infected individualhas AIDS-related complex (ARC). In some embodiments, the individual inneed thereof is undergoing immunosuppressive therapy. In someembodiments, the individual in need thereof is undergoingimmunosuppressive therapy after organ transplantation.

One aspect of the present invention encompasses methods for treatinghypertension in an individual comprising administering to the individualin need thereof a therapeutically effective amount of a compoundaccording to any of the embodiments described herein or a pharmaceuticalcomposition thereof.

One aspect of the present invention encompasses methods for treatingpain in an individual comprising administering to the individual in needthereof a therapeutically effective amount of a compound according toany of the embodiments described herein or a pharmaceutical compositionthereof.

One aspect of the present invention encompasses processes for preparinga composition comprising admixing a compound according any embodimentsdescribed herein and a pharmaceutically acceptable carrier.

One aspect of the present invention is the use of a compound of thepresent invention for the production of a medicament for use in thetreatment of a 5-HT_(2A) mediated disorder.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is platelet aggregation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of one or moreconditions associated with platelet aggregation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is selected from the groupconsisting of coronary artery disease, myocardial infarction, transientischemic attack, angina, stroke, and atrial fibrillation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is a blood clot formation in anangioplasty or coronary bypass surgery individual.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is a blood clot formation in anindividual suffering from atrial fibrillation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a sleep disorder,such as those disclosed herein.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a dyssomnia.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a parasomnia.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of adiabetic-related disorder.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is asthma.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is a symptom of asthma.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is agitation or a symptom thereofin an individual. In some embodiments the individual is a cognitivelyintact elderly individual.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is agitation or a symptom thereofin an individual suffering from dementia. In some embodiments thedementia is due to a degenerative disease of the nervous system. In someembodiments the dementia is Alzheimers disease, Lewy Body, Parkinson'sdisease, or Huntington's disease. In some embodiments the dementia isdue to diseases that affect blood vessels. In some embodiments thedementia is due to stroke or multi-infract dementia.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder further comprising a dopamine D₂ receptor antagonistwherein the disorder is selected from the group consisting of abehavioral disorder, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorder, organic or NOSpsychosis, psychotic disorder, psychosis, acute schizophrenia, chronicschizophrenia and NOS schizophrenia. In some embodiments the dopamine D₂receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder further comprising a dopamine D₂ receptor antagonistwherein the disorder is infantile autism, Huntington's chorea, or nauseaand vomiting from chemotherapy or chemotherapeutic antibodies. In someembodiments the dopamine D₂ receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder further comprising a dopamine D₂ receptor antagonistwherein the disorder is schizophrenia. In some embodiments the dopamineD₂ receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is a negative symptom or symptomsof schizophrenia induced by the administration of haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the haloperidol and the compound orpharmaceutical composition are administered in separate dosage forms.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the haloperidol and the compound orpharmaceutical composition are administered in a single dosage form.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is progressive multifocalleukoencephalopathy.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of hypertension.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of pain.

One aspect of the present invention pertains to compounds according toany of the embodiments described herein for use in a method of treatmentof the human or animal body by therapy.

One aspect of the present invention pertains to compounds according toany of the embodiments described herein for use in a method for thetreatment of a 5-HT_(2A) mediated disorder, as described herein, in thehuman or animal body by therapy.

One aspect of the present invention pertains to compounds according toany of the embodiments described herein for use in a method for thetreatment of a sleep disorder, as described herein, in the human oranimal body by therapy.

One aspect of the present invention pertains to compounds according toany of the embodiments described herein for use in a method for thetreatment of platelet aggregation in the human or animal body bytherapy.

One aspect of the present invention pertains to compounds according toany of the embodiments described herein for use in a method for thetreatment of one of more conditions associated with platelet aggregationin the human or animal body by therapy.

One aspect of the present invention pertains to compounds according toany of the embodiments described herein for use in a method for thetreatment of progressive multifocal leukoencephalopathy in the human oranimal body by therapy.

One aspect of the present invention pertains to compounds according toany of the embodiments described herein for use in a method of treatmentof hypertension in the human or animal body by therapy.

One aspect of the present invention pertains to compounds according toany of the embodiments described herein for use in a method of treatmentof pain in the human or animal body by therapy.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention. FIG. 1 shows a generalcoupling method between a pyrazole boronic acid and an aryl triflate, itis understood that similar coupling methods known in the art can also beused, and a halide, such as, I, Br or Cl, can be used in place of thetriflate.

FIG. 2 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention wherein “V” is oxygen.FIG. 2 shows a general coupling method between a pyrazole boronic acidand a phenyl halide using coupling methods known in the art, such as aSuzuki coupling, and the like. FIG. 2 further shows the use oforthogonal protecting groups for the oxygen (V═O) and the nitrogen.After the coupling reaction the phenol protecting group is removed and avariety of —W—R₄ groups can be introduced. Subsequently, the alkyl amideprotecting group can be hydrolyzed to provide the amine intermediate ofthe present invention.

FIG. 3 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention. FIG. 3 shows a generalcoupling method between a 2-substituted pyrazol-3-yl-boronic acid and anaryl triflate, it is understood that similar coupling methods known inthe art can also be used, and a halide, such as, I, Br or Cl, can beused in place of the triflate.

FIG. 4 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention. FIG. 4 shows thegeneral reaction of hydrazines with substituted chromen-4-ones toprepare certain 2-(pyrazol-3-yl)-phenols. Further shown in FIG. 4 arethe general alkylation reactions for introducing the W—R₄ group.

FIG. 5 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention. FIG. 5 illustratesgeneral methods for introducing a variety of halogens to compounds ofthe invention. It is understood that these halogenation reaction canalso be conducted later in the synthesis, for example as the last step.

FIG. 6 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention. FIG. 6 shows thegeneral reactions, such as, alkylation and Mitsunobu-like reactions, forintroducing the W—R₄ group.

FIG. 7 shows the general synthetic scheme for the preparation ofcompounds of the present invention. FIG. 7 shows the general couplingreactions of the aniline intermediate with a variety of electrophils,such as, carboxylic acids, acyl halides, isocyanates, isothiocyanates,haloformates, and the like.

FIG. 8 shows the general synthetic scheme for the preparation ofintermediates and compounds of the present invention.

FIG. 9 shows the general reaction for the preparation of diaryl aminesand heteroaryl-aryl amines. FIG. 9 illustrates the coupling of theaniline intermediate with heteroaryl-halo or aryl-halo to give diarylamines and heteroaryl-aryl amines of the present invention.

FIG. 10 shows the general synthetic scheme for the preparation ofcompounds of the invention wherein the W—R₄ group is introduced in thelast step(s). FIG. 10 shows the general reactions, such as, alkylationand Mitsunobu-like reactions, for introducing the W—R₄ group.

FIG. 11 shows the general synthetic scheme for the preparation ofcompounds of the invention wherein V is S or NR₁₀ and the W—R₄ group isintroduced in the last step(s). FIG. 11 shows the general reactions,such as, alkylation reactions, for introducing the W—R₄ group wherein Vis S or NR₁₀.

FIG. 12 shows the general synthetic scheme for the preparation ofcompounds of the invention wherein V is S(O) or S(O)₂.

DEFINITIONS

The scientific literature that has evolved around receptors has adopteda number of terms to refer to ligands having various effects onreceptors. For clarity and consistency, the following definitions willbe used throughout this patent document.

AGONISTS shall mean moieties that interact and activate the receptor,such as the 5-HT_(2A) receptor, and initiates a physiological orpharmacological response characteristic of that receptor. For example,when moieties activate the intracellular response upon binding to thereceptor, or enhance GTP binding to membranes.

The term ANTAGONISTS is intended to mean moieties that competitivelybind to the receptor at the same site as agonists (for example, theendogenous ligand), but which do not activate the intracellular responseinitiated by the active form of the receptor, and can thereby inhibitthe intracellular responses by agonists or partial agonists. Antagonistsdo not diminish the baseline intracellular response in the absence of anagonist or partial agonist.

CHEMICAL GROUP, MOIETY OR RADICAL:

The term “C₁₋₆ acyl” denotes a C₁₋₆ alkyl radical attached to a carbonylwherein the definition of alkyl has the same definition as describedherein; some examples include, but are not limited to, acetyl,propionyl, n-butanoyl, iso-butanoyl, sec-butanoyl, t-butanoyl (i.e.,pivaloyl), pentanoyl and the like.

The term “C₁₋₁₂ acyloxy” denotes an acyl radical attached to an oxygenatom wherein acyl has the same definition has described herein; someembodiments are when acyloxy is C₁₋₁₁ acyloxy, some embodiments are whenacyloxy is C₁₋₁₀ acyloxy, some embodiments are when acyloxy is C₁₋₈acyloxy, some embodiments are when acyloxy is C₁₋₆ acyloxy, someembodiments are when acyloxy is C₁₋₅ acyloxy, some embodiments are whenacyloxy is C₁₋₄ acyloxy, some embodiments are when acyloxy is C₁₀₋₁₂acyloxy, some embodiments are when acyloxy is C₈₋₁₀ acyloxy. Someexamples include, but are not limited to, acetyloxy, propionyloxy,butanoyloxy, iso-butanoyloxy, sec-butanoyloxy, t-butanoyloxy,pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy,decanoyloxy, undecanoyloxy, dodecanoyloxy, tridecanoyloxy, and the like.

The term “C₂₋₆ alkenyl” denotes a radical containing 2 to 6 carbonswherein at least one carbon-carbon double bond is present, someembodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, andsome embodiments have 2 carbons. Both E and Z isomers are embraced bythe term “alkenyl.” Furthermore, the term “alkenyl” includes di- andtri-alkenyls. Accordingly, if more than one double bond is present thenthe bonds may be all E or Z or a mixtures of E and Z. Examples of analkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl,2,4-hexadienyl and the like.

The term “C₁₋₆ alkoxy” as used herein denotes an alkyl radical, asdefined herein, attached directly to an oxygen atom. Examples includemethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy,sec-butoxy and the like.

The term “C₁₋₆ alkoxycarbonylamino” denotes the group represented by theformula:

wherein C₁₋₆ alkyl has the same definition as found herein. Examples ofC₁₋₆ alkoxycarbonylamino include methoxycarbonylamino,ethoxycarbonylamino, isopropoxycarbonylamino, propoxycarbonylamino,tert-butoxycarbonylamino, butoxycarbonylamino, and the like.

The term “C₁₋₈ alkyl” denotes a straight or branched carbon radicalcontaining 1 to 8 carbons, some embodiments are 1 to 6 carbons, someembodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons, andsome embodiments are 1 or 2 carbons. Examples of an alkyl include, butare not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, t-butyl, pentyl, iso-pentyl, t-pentyl, neo-pentyl,1-methylbutyl [i.e., —CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e.,—CH₂CH(CH₃)CH₂CH₃], n-hexyl and the like.

The term “C₁₋₆ alkylcarboxamido” or “C₁₋₆ alkylcarboxamide” denotes asingle C₁₋₆ alkyl group attached to the nitrogen of an amide group,wherein alkyl has the same definition as found herein. The C₁₋₆alkylcarboxamido may be represented by the following:

Examples include, but are not limited to, N-methylcarboxamide,N-ethylcarboxamide, N-n-propylcarboxamide, N-iso-propylcarboxamide,N-n-butylcarboxamide, N-sec-butylcarboxamide, N-iso-butylcarboxamide,N-t-butylcarboxamide and the like.

The term “C₁₋₄ alkylene” refers to a C₁₋₄ divalent straight carbon groupcontaining 1 to 4 carbons, some embodiments are 1 to 3 carbons, someembodiments are 1 to 2 carbons. In some embodiments alkylene refers to,for example, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

The term “C₁₋₆ alkylsulfinyl” denotes a C₁₋₆ alkyl radical attached to asulfoxide radical of the formula: —S(O)— wherein the alkyl radical hasthe same definition as described herein. Examples include, but are notlimited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,iso-propylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl,iso-butylsulfinyl, t-butylsulfinyl, and the like.

The term “C₁₋₆ alkylsulfonamide” refers to the groups shown below:

-   -   Error! Objects cannot be created from editing field codes.        wherein C₁₋₆ alkyl has the same definition as described herein.

The term “C₁₋₆ alkylsulfonyl” denotes a C₁₋₆ alkyl radical attached to asulfone radical of the formula: —S(O)₂— wherein the alkyl radical hasthe same definition as described herein. Examples include, but are notlimited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,iso-butylsulfonyl, t-butylsulfonyl, and the like.

The term “C₁₋₆ alkylthio” denotes a C₁₋₆ alkyl radical attached to asulfide of the formula: —S— wherein the alkyl radical has the samedefinition as described herein. Examples include, but are not limitedto, methylsulfanyl (i.e., CH₃S—), ethylsulfanyl, n-propylsulfanyl,iso-propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl,iso-butylsulfanyl, t-butylsulfanyl, and the like.

The term “C₁₋₆ alkylthiocarboxamide” denotes a thioamide of thefollowing formulae:

wherein C₁₋₄ alkyl has the same definition as described herein.

The term “C₁₋₆ alkylureyl” denotes the group of the formula: —NC(O)N—wherein one are both of the nitrogens are substituted with the same ordifferent C₁₋₆ alkyl group wherein alkyl has the same definition asdescribed herein. Examples of an alkylureyl include, but are not limitedto, CH₃NHC(O)NH—, NH₂C(O)NCH₃—, (CH₃)₂NC(O)NH—, (CH₃)₂NC(O)NH—,(CH₃)₂NC(O)NCH₃—, CH₃CH₂NHC(O)NH—, CH₃CH₂NHC(O)NCH₃—, and the like.

The term “C₂₋₆ alkynyl” denotes a radical containing 2 to 6 carbons andat least one carbon-carbon triple bond, some embodiments are 2 to 4carbons, some embodiments are 2 to 3 carbons, and some embodiments have2 carbons. Examples of an alkynyl include, but are not limited to,ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl and the like. The term “alkynyl”includes di- and tri-ynes.

The term “amino” denotes the group —NH₂.

The term “C₁₋₆ alkylamino” denotes one alkyl radical attached to anamino radical wherein the alkyl radical has the same meaning asdescribed herein. Some examples include, but are not limited to,methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino,sec-butylamino, iso-butylamino, t-butylamino, and the like. Someembodiments are “C₁₋₂ alkylamino.”

The term “aryl” denotes an aromatic ring radical containing 6 to 10 ringcarbons. Examples include phenyl and naphthyl.

The term “arylalkyl” defines a C₁-C₄ alkylene, such as —CH₂—, —CH₂CH₂—and the like, which is further substituted with an aryl group. Examplesof an “arylalkyl” include benzyl, phenethylene and the like.

The term “arylcarboxamido” denotes a single aryl group attached to thenitrogen of an amide group, wherein aryl has the same definition asfound herein. The example is N-phenylcarboxamide.

The term “arylureyl” denotes the group —NC(O)N— where one of thenitrogens are substituted with an aryl.

The term “benzyl” denotes the group —CH₂C₆H₅.

The term “bicyclic” refers to two C₄₋₇ cyclalkyl groups that share tworing carbons thus forming either a fused or bridged ring. Bicyclicexamples include, but not limited to, bicyclo[1.1.1]pentyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, and the like.

The term “carbo-C₁₋₆-alkoxy” refers to a C₁₋₆ alkyl ester of acarboxylic acid, wherein the alkyl group is as defined herein. Examplesinclude, but are not limited to, carbomethoxy, carboethoxy,carbopropoxy, carboisopropoxy, carbobutoxy, carbo-sec-butoxy,carbo-iso-butoxy, carbo-t-butoxy, carbo-n-pentoxy, carbo-iso-pentoxy,carbo-t-pentoxy, carbo-neo-pentoxy, carbo-n-hexyloxy, and the like.

The term “carboxamide” refers to the group —CONH₂.

The term “carboxy” or “carboxyl” denotes the group —CO₂H; also referredto as a carboxylic acid group.

The term “cyano” denotes the group —CN.

The term “C₄₋₇ cycloalkenyl” denotes a non-aromatic ring radicalcontaining 4 to 7 ring carbons and at least one double bond; someembodiments contain 4 to 6 carbons; some embodiments contain 4 to 5carbons; some embodiments contain 4 carbons. Examples includecyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl, and the like.

The term “C₃₋₇ cycloalkyl” denotes a saturated ring radical containing 3to 7 carbons; some embodiments contain 3 to 6 carbons; some embodimentscontain 3 to 5 carbons; some embodiments contain 5 to 7 carbons; someembodiments contain 3 to 4 carbons. Examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

The term “C₃₋₇ cycloalkylcarbonyl” denotes a C₃₋₇ cycloalkyl group, asdescribed herein, bonded to the carbon of a carbonyl group (i.e.,—C(═O)—). Examples of the C₃₋₇ cycloalkylcarbonyl group include, but notlimited to, cyclopropylcarbonyl, cyclobutylcarbonyl,cyclopentylcarbonyl, and the like.

The term “C₃₋₆ cycloalkylene” refers to a divalent cycloalkyl radical,where cycloalkyl is as defined herein, containing 3 to 6 carbons; someembodiments contain 3 to 5 carbons; some embodiments contain 3 to 4carbons. In some embodiments, the C₃₋₆ cycloalkylene group has the twobonding groups on the same ring carbon, for example:

In some embodiments, the C₃₋₆ cycloalkylene group has the two bondinggroups on different ring carbons. It is understood that when the twogroups of the C₃₋₆ cycloalkylene group are on different ring carbonsthey may be cis or trans or mixtures thereof with respect to each other.

The term “C₂₋₈ dialkylamino” denotes an amino substituted with two ofthe same or different C₁₋₄ alkyl radicals wherein alkyl radical has thesame definition as described herein. Some examples include, but are notlimited to, dimethylamino, methylethylamino, diethylamino,methylpropylamino, methylisopropylamino, ethylpropylamino,ethylisopropylamino, dipropylamino, propylisopropylamino and the like.Some embodiments are “C₂₋₄ dialkylamino.”

The term “C₂₋₈ dialkylcarboxamido” or “C₂₋₈ dialkylcarboxamide” denotestwo alkyl radicals, that are the same or different, attached to an amidegroup, wherein alkyl has the same definition as described herein. A C₂₋₈dialkylcarboxamido may be represented by the following groups:

wherein C₁₋₄ has the same definition as described herein. Examples of adialkylcarboxamide include, but are not limited to,N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide,N,N-diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.

The term “C₂₋₈ dialkylsulfonamide” refers to one of the following groupsshown below:

wherein C₁₋₄ has the same definition as described herein, for examplebut are not limited to, methyl, ethyl, n-propyl, isopropyl, and thelike.

The term “C₂₋₈ dialkylthiocarboxamido” or “C₂₋₈ dialkylthiocarbox-amide”denotes two alkyl radicals, that are the same or different, attached toa thioamide group, wherein alkyl has the same definition as describedherein. A C₂₋₈ dialkylthiocarboxamido or C₂₋₈ dialkylthiocarboxamide maybe represented by the following groups:

Examples of a dialkylthiocarboxamide include, but are not limited to,N,N-dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide and thelike.

The term “formyl” refers to the group —CHO.

The term “C₁₋₆ haloalkoxy” denotes a C₁₋₆ haloalkyl, as defined herein,which is directly attached to an oxygen atom. Examples include, but arenot limited to, difluoromethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy and the like.

The term “C₁₋₆ haloalkyl” denotes an C₁₋₆ alkyl group, defined herein,wherein the alkyl is substituted with one halogen up to fullysubstituted and a fully substituted C₁₋₆ haloalkyl can be represented bythe formula C_(n)L_(2n+1) wherein L is a halogen and “n” is 1, 2, 3, 4,5 or 6; when more than one halogen is present then they may be the sameor different and selected from the group consisting of F, Cl, Br and I,preferably F. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl,2,2,2-trifluoroethyl, pentafluoroethyl and the like.

The term “C₁₋₆ haloalkylcarboxamide” denotes an C₁₋₆ alkylcarboxamidegroup, defined herein, wherein the alkyl is substituted with one halogenup to fully substituted represented by the formula C_(n)L_(2n+1) whereinL is a halogen and “n” is 1, 2, 3, 4, 5 or 6. When more than one halogenis present they may be the same or different and selected from the groupconsisting of F, Cl, Br and I, preferably F.

The term “C₁₋₆ haloalkylsulfinyl” denotes a C₁₋₆ haloalkyl radicalattached to a sulfoxide group of the formula: —S(O)— wherein thehaloalkyl radical has the same definition as described herein. Examplesinclude, but are not limited to, trifluoromethylsulfinyl,2,2,2-trifluoroethylsulfinyl, 2,2-difluoroethylsulfinyl and the like.

The term “C₁₋₆ haloalkylsulfonyl” denotes a C₁₋₆ haloalkyl radicalattached to a sulfone group of the formula: —S(O)₂— wherein haloalkylhas the same definition as described herein. Examples include, but arenot limited to, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl,2,2-difluoroethylsulfonyl and the like.

The term “C₁₋₆ haloalkylthio” denotes a C₁₋₆ haloalkyl radical directlyattached to a sulfur wherein the haloalkyl has the same meaning asdescribed herein. Examples include, but are not limited to,trifluoromethylthio (i.e., CF₃S—, also referred to astrifluoromethylsulfanyl), 1,1-difluoroethylthio,2,2,2-trifluoroethylthio and the like. The term “halogen” or “halo”denotes to a fluoro, chloro, bromo or iodo group.

The term “heteroaryl” denotes an aromatic ring system that may be asingle ring, two fused rings or three fused rings wherein at least onering carbon is replaced with a heteroatom selected from, but not limitedto, the group consisting of O, S and N wherein the N can be optionallysubstituted with H, C₁₋₄ acyl or C₁₋₄ alkyl. Examples of heteroarylgroups include, but are not limited to, pyridyl, benzofuranyl,pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl,benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, isoquinolinyl,quinazolinyl, quinoxalinyl and the like. In some embodiments, theheteroatom is selected from, but not limited to, the group consisting ofO, S and N, wherein N is substituted with H (i.e., NH), examplesinclude, but are not limited to, pyrrolyl, indolyl,1H-benzoimidazol-2-yl, and the like. Other examples include, but are notlimited to, those in TABLE 1, TABLE 2, and the like.

The term “heterobicyclic” denotes a non-aromatic bicyclic ring, asdescribed herein, wherein 1, 2, or 3 ring carbons are replaced with aheteroatom selected from, but are not limited to, the group consistingof O, S, S(═O), S(═O)₂, and NH, wherein the nitrogen can be optionallysubstituted, and 1 or 2 ring carbons can be optionally substituted withoxo or thiooxo thus together form a carbonyl or thiocarbonyl grouprespectively. Examples of a heterobicyclic group include, but are notlimited to, 2,5-diaza-bicyclo[2.2.1]hept-2-yl,7-aza-bicyclo[2.2.1]hept-7-yl, and the like.

The term “heterocyclic” denotes a non-aromatic carbon ring (i.e., C₃₋₇cycloalkyl or C₄₋₇ cycloalkenyl as defined herein) wherein one, two orthree ring carbons are replaced by a heteroatom selected from, but arenot limited to, the group consisting of O, S, S(═O), S(═O)₂, NH, whereinthe N can be optionally substituted as described herein, in someembodiments, the nitrogen is optionally substituted with C₁₋₄ acyl orC₁₋₄ alkyl, and ring carbon atoms optionally substituted with oxo or athiooxo thus forming a carbonyl or thiocarbonyl group. The heterocyclicgroup can be attached/bonded to any available ring atom, for example,ring carbon, ring nitrogen, and the like. The heterocyclic group is a3-, 4-, 5-, 6- or 7-membered containing ring. Examples of a heterocyclicgroup include, but are not limited to, aziridin-1-yl, aziridin-2-yl,azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, piperidin-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl,morpholin-3-yl, morpholin-4-yl, piperzin-1-yl, piperzin-2-yl,piperzin-3-yl, piperzin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, [1,3]-dioxolan-2-yl, thiomorpholin-4-yl,[1,4]oxazepan-4-yl, 1,1-dioxo-1λ⁶-thiomorpholin-4-yl, azepan-1-yl,azepan-2-yl, azepan-3-yl, azepan-4-yl, and the like.

The term “hydroxyl” refers to the group —OH.

The term “nitro” refers to the group —NO₂.

As used herein, the term “oxo” refers to the substituent ═O,accordingly, when a carbon is substituted by an oxo group the new groupresulting from the carbon and oxo together is a carbonyl group.

The term “phenoxy” refers to the group C₆H₅O—.

The term “phenyl” refers to the group C₆H₅—.

The term“sulfonic acid” refers to the group —SO₃H.

The term “thiol” denotes the group —SH.

COMPOSITION shall mean a material comprising at least two compounds ortwo components; for example, and without limitation, a PharmaceuticalComposition is a Composition comprising a compound of the presentinvention and a pharmaceutically acceptable carrier.

CONTACT or CONTACTING shall mean bringing the indicated moietiestogether, whether in an in vitro system or an in vivo system. Thus,“contacting” a 5-HT_(2A) receptor with a compound of the inventionincludes the administration of a compound of the present invention to anindividual, preferably a human, having a 5-HT_(2A) receptor, as well as,for example, introducing a compound of the invention into a samplecontaining a cellular or more purified preparation containing a5-HT_(2A) receptor.

IN NEED OF TREATMENT as used herein refers to a judgment made by acaregiver (e.g. physician, nurse, nurse practitioner, etc. in the caseof humans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual or animal is ill, or will become ill, as the resultof a disease, condition or disorder that is treatable by the compoundsof the invention. Accordingly, the compounds of the invention can beused in a protective or preventive manner; or compounds of the inventioncan be used to alleviate, inhibit or ameliorate the disease, conditionor disorder.

INDIVIDUAL as used herein refers to any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates, and most preferably humans.

INHIBIT or INHIBITING, in relationship to the term “response” shall meanthat a response is decreased or prevented in the presence of a compoundas opposed to in the absence of the compound.

INVERSE AGONISTS shall mean moieties that bind the endogenous form ofthe receptor or to the constitutively activated form of the receptor,and which inhibit the baseline intracellular response initiated by theactive form of the receptor below the normal base level of activitywhich is observed in the absence of agonists or partial agonists, ordecrease GTP binding to membranes. Preferably, the baselineintracellular response is inhibited in the presence of the inverseagonist by at least 30%, more preferably by at least 50%, and mostpreferably by at least 75%, as compared with the baseline response inthe absence of the inverse agonist.

As used herein, the terms MODULATE or MODULATING shall mean to refer toan increase or decrease in the amount, quality, response or effect of aparticular activity, function or molecule.

PHARMACEUTICAL COMPOSITION shall mean a composition comprising at leastone active ingredient; including but not limited to, salts, solvates andhydrates of compounds of Formula (Ia); whereby the composition isamenable to investigation for a specified, efficacious outcome in amammal (for example, without limitation, a human). Those of ordinaryskill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

THERAPEUTICALLY EFFECTIVE AMOUNT as used herein refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician, which includes one or more of the following:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease,

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and

(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

COMPOUNDS OF THE INVENTION

One aspect of the present invention encompasses certain3-phenyl-pyrazole derivatives as shown in Formula (Ia):

or a pharmaceutically acceptable salt, hydrate or solvate thereof;wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, V, W, X, Y and Z have thesame definitions as described herein, supra and infra, provided that thecompound is notN-[4-oxiranylmethoxy-3-(2H-pyrazol-3-yl)-phenyl]-acetamide:

In some embodiments, the present invention pertains to compounds ofFormula (Ia), as described herein, or a pharmaceutically acceptablesalt, hydrate, solvate, or N-oxide thereof.

In some embodiments, the present invention pertains to compounds whereinthe R₄ group contains an N-oxide.

In some embodiments, the present invention pertains to certain3-phenyl-pyrazole derivatives as shown in Formula (Ia):

or a pharmaceutically acceptable salt thereof;

wherein:

V is O, S, S(═O), S(═O)₂ or NR₁₀;

W is C₁₋₄ alkylene optionally substituted with 1 to 8 substituentsselected independently from the group consisting of C₁₋₃ alkyl, C₁₋₄alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, halogen and oxo; or W is absent;

X is C(═O), C(═S) or absent;

Y is O, NR₁₁ or absent;

Z is C₁₋₄ alkylene optionally substituted with 1 to 8 substituentsselected independently from the group consisting of C₁₋₃ alkyl, C₁₋₄alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, halogen and oxo; or Z is absent;

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₃₋₇ cycloalkyl;

R₂ is selected from the group consisting of H, C₁₋₆ acyl, C₁₋₆ acyloxy,C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₂₋₈ dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen,C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, thiol, nitro andsulfonamide;

R₃ is selected from the group consisting of H, C₂₋₆ alkenyl, C₁₋₆ alkyl,C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each ofthe C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₃₋₇cycloalkyl, heteroaryl and phenyl groups are optionally substituted with1 to 5 substituents selected independently from the group consisting ofC₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₆alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, nitro and sulfonamide;

R₄ is heterocyclic or heteroaryl each optionally substituted withsubstituents selected independently from the group consisting of C₁₋₆acyl, C₁₋₁₂ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₆alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, nitro and sulfonamide;wherein C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, andcarbo-C₁₋₆-alkoxy are each optionally substituted with substituentsselected independently from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, andphenyl;

R₅, R₆, and R₇ are each selected independently from the group consistingof H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkylimino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆haloalkylthio, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenyl;

R₈ is C₁₋₈ alkyl, C₂₋₆ alkenyl, aryl or heteroaryl each optionallysubstituted with substituents selected independently from the groupconsisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkylimino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆haloalkylthio, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenylor two adjacent substituents together with aryl or heteroaryl form aC₅₋₇ cycloalkyl optionally comprising 1 to 2 oxygen atoms optionallysubstituted with F, Cl or Br; and wherein C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆alkynyl, C₁₋₆ alkylamino, C₁₋₆ alkylimino, C₂₋₈ dialkylamino,heterocyclic, and phenyl are each optionally substituted with 1 to 5substituents selected independently from the group consisting of C₁₋₆acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylcarboxamide,halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, thiol and nitro; and

R₉, R₁₀, and R₁₁ are each independently H or C₁₋₈ alkyl;

provided that the compound is other thanN-[4-oxiranylmethoxy-3-(2H-pyrazol-3-yl)-phenyl]-acetamide.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g.,R₁, R₂, R₃, R₄, X, Y, Z, etc.) contained within the generic chemicalformulae described herein [e.g. (Ia), (Ic), (Ie), etc.] are specificallyembraced by the present invention just as if they were explicitlydisclosed, to the extent that such combinations embrace compounds thatresult in stable compounds (ie., compounds that can be isolated,characterized and tested for biological activity). In addition, allsubcombinations of the chemical groups listed in the embodimentsdescribing such variables, as well as all subcombinations of uses andmedical indications described herein, are also specifically embraced bythe present invention just as if each of such subcombination of chemicalgroups and subcomination of uses and medical indications were explicitlydisclosed herein.

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup, the non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valance of substitution; for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.Likewise, “substituted with one or more substituents” refers to thesubstitution of a group with one substituent up to the total number ofsubstituents physically allowed by the group. Further, when a group issubstituted with more than one group they can be identical or they canbe different.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers, and the like. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution. It is understood that the various tautomeric forms arewithin the scope of the compounds of the present invention.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates and/or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include deuterium and tritium.

It is understood and appreciated that compounds of the present inventionmay have one or more chiral centers, and therefore can exist asenantiomers and/or diastereomers. The invention is understood to extendto and embrace all such enantiomers, diastereomers and mixtures thereof,including but not limited, to racemates. Accordingly, some embodimentsof the present invention pertain to compounds of the present inventionthat are R enantiomers. Further, some embodiments of the presentinvention pertain to compounds of the present invention that are Senantiomers. In examples where more than one chiral center is present,then, some embodiments of the present invention include compounds thatare RS or SR enantiomers. In further embodiments, compounds of thepresent invention are RR or SS enantiomers. It is understood thatcompounds of the present invention are intended to represent allpossible individual enantiomers and mixtures thereof just as if if eachhad been individually named with the structure provided, unless statedor shown otherwise.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in the following Formula (Ic):

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Ie):

In some embodiments, V is O.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Ig):

wherein each variable in Formula (Ig) has the same meaning as describedherein, supra and infra.

In some embodiments, W is C₁₋₄ alkylene optionally substituted with oxo.

In some embodiments, W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)—, —CH₂CH₂CH₂—,—C(CH₃)₂C(═O)—, —CH₂CH(CH₃)—, —CH(CH₃)CH₂—, —C(CH₃)₂CH₂—, or—CH₂C(CH₃)₂—.

In some embodiments, W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)— or —CH₂CH₂CH₂—.

In some embodiments, W is —CH₂CH₂—.

In some embodiments, W is absent.

In some embodiments, X is C(═O).

In some embodiments, X is absent.

In some embodiments, Y is NH, O or absent.

In some embodiments, Y is NH or absent.

In some embodiments, Y is NH.

In some embodiments, Y is O.

In some embodiments, Y is absent.

In some embodiments, Z is C₁₋₄ alkylene or C₃₋₆ cycloalkylene optionallysubstituted with 1, 2, 3, or 4 substituents selected independently fromthe group consisting of C₁₋₃ alkyl, halogen, and oxo.

In some embodiments, Z is absent, —CH₂—, —CH(OH)—, —CF₂—, —C(CH₃)₂—,1,1-cyclopropyl, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—, or —C(═O)—.

In some embodiments, Z is absent, —CH₂— or —CH(OH)—.

In some embodiments, Z is absent or —CH₂—.

In some embodiments, Z is absent.

In some embodiments, R₁ is C₁₋₆ alkyl.

In some embodiments, R₁ is —CH₃.

In some embodiments, R₁ is H.

It is understood when R₁ is H that tautomers are possible. It is wellunderstood and appreciated in the art that pyrazoles can exist invarious tautomeric forms. Two possible tautomeric forms are illustratedbelow:

It is further understood that tautomeric forms can also havecorresponding nomenclature for each represented tautomer, for example,the pyrazol-3-yl groups in Formula (Ii) and Formula (Ii′) can berepresented by the general chemical names 1H-pyrazol-3-yl and2H-pyrazol-3-yl respectively. Therefore, the present invention includesall tautomers and the various nomenclature designations.

In some embodiments, R₂ is H.

In some embodiments, R₃ is H or halogen.

In some embodiments, R₃ is H, F, Cl or Br.

In some embodiments, R₃ is H, Cl or Br.

In some embodiments, R₃ is H.

In some embodiments, R₄ is a group other than an oxiranyl group.

In some embodiments, R₄ is heterobicyclic, heterocyclic, or heteroaryleach optionally substituted with substituents selected independentlyfrom the group consisting of C₁₋₆ acyl, C₁₋₁₂ acyloxy, C₂₋₆ alkenyl,C₁₋₄ alkoxy, C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₂₋₈dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, formyl,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heteroaryl, hydroxyl, nitro,phenyl and sulfonamide; wherein said C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, amino, carbo-C₁₋₆-alkoxy, andheteroaryl are each optionally substituted with substituents selectedindependently from the group consisting of C₁₋₆ alkyl, C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, andphenyl.

In some embodiments, R₄ is heterobicyclic, heterocyclic or heteroaryleach optionally substituted with substituents selected independentlyfrom the group consisting of C₁₋₆ acyl, C₁₋₁₂ acyloxy, C₁₋₄ alkoxy, C₁₋₆alkoxycarbonylamino, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆cycloalkyl, C₂₋₆ dialkylcarboxamide, formyl, halogen, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, heteroaryl, hydroxyl and phenyl; wherein said C₁₋₅ acyl,C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, amino,carbo-C₁₋₆-alkoxy and heteroaryl are each optionally substituted withsubstituents selected independently from the group consisting of C₁₋₆alkyl, C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, hydroxyl, and phenyl

In some embodiments, R₄ is heterobicyclic, heterocyclic, or heteroaryleach optionally substituted with substituents selected independentlyfrom the group consisting of C₁₋₆ acyl, C₁₋₁₂ acyloxy, C₁₋₆alkoxycarbonylamino, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide,C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, C₂₋₆ dialkylcarboxamide,formyl, halogen, C₁₋₄ haloalkyl, heteroaryl, hydroxyl and phenyl;wherein said C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₄alkylcarboxamide, amino, carbo-C₁₋₆-alkoxy and heteroaryl are eachoptionally substituted with substituents selected independently from thegroup consisting of C₁₋₆ alkyl, carbo-C₁₋₆-alkoxy, carboxy, and phenyl.

In some embodiments, R₄ is heterocyclic or heteroaryl each optionallysubstituted with substituents selected independently from the groupconsisting of C₁₋₆ acyl, C₁₋₁₂ acyloxy, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₆alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonyl, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, and hydroxyl; wherein C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₆ alkyl,C₁₋₄ alkylcarboxamide, and carbo-C₁₋₆-alkoxy are each optionallysubstituted with C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₆ alkylamino, C₂₋₈dialkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, and phenyl.

In some embodiments, R₄ is heterocyclic or heteroaryl each optionallysubstituted with substituents selected independently from the groupconsisting of C₁₋₆ acyl, C₁₋₁₂ acyloxy, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxy,and hydroxyl; wherein C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₆ alkyl, C₁₋₄alkylcarboxamide, and carbo-C₁₋₆-alkoxy are each optionally substitutedwith carbo-C₁₋₆-alkoxy, carboxy, and phenyl.

In some embodiments, heteroaryl is a 5-membered heteroaryl, for example,a 5-membered heteroaryl as shown in TABLE 1:

TABLE 1

wherein the 5-membered heteroaryl is bonded at any available position ofthe ring, for example, a imidazolyl ring can be bonded at one of thering nitrogens (i.e., imidazol-1-yl group) or at one of the ring carbons(i.e., imidazol-2-yl, imidazol-4-yl or imiadazol-5-yl group).

In some embodiments, heteroaryl is a 6-membered heteroaryl, for example,a 6-membered heteroaryl as shown in TABLE 2:

TABLE 2

wherein the heteroaryl group is bonded at any ring carbon.

In some embodiments, R₄ is selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl,azetidinyl, thiomorpholinyl 2,5-diaza-bicyclo[2.2.1]heptyl,[1,4]oxazepanyl, 1,1-dioxo-1λ⁶-thiomorpholinyl, azepanyl, and3-oxo-piperazinyl, aza-bicyclo[2.2.1]heptyl, and imidazolyl eachoptionally substituted with substituents selected independently from thegroup consisting of C₁₋₆ acyl, C₁₋₁₂ acyloxy, C₁₋₄ alkoxy, C₁₋₆alkoxycarbonylamino, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, C₂₋₆ dialkylcarboxamide,formyl, halogen, C₁₋₄ haloalkyl, heteroaryl, hydroxyl and phenyl;wherein said C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₄alkylcarboxamide, amino, carbo-C₁₋₆-alkoxy and heteroaryl are eachoptionally substituted with substituents selected independently from thegroup consisting of C₁₋₆ alkyl, carbo-C₁₋₆-alkoxy, carboxy, and phenyl.

In some embodiments, R₄ is selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl,azetidinyl, thiomorpholinyl, 2,5-diaza-bicyclo[2.2.1]heptyl,[1,4]oxazepanyl, 1,1-dioxo-1λ⁶-thiomorpholinyl, azepanyl,3-oxo-piperazinyl, 7-aza-bicyclo[2.2.1]hept-7-yl, and imidazolyl eachoptionally substituted with substituents selected independently from thegroup consisting of CH₃, C(═O)O-t-butyl, C(═O)OH, C(═O)OEt,NHC(═O)O-t-butyl, OH, C(═O)NHCH₂C(═O)OCH₃, NHC(═O)CH₂C(═O)OCH₃,C(═O)NHCH₂C(═O)OH, NHC(═O)CH₂C(═O)OH, C(═O)OCH₃, OC(═O)CH₂CH₂C(═O)OCH₃,OC(═O)CH₂CH₂CH₂CH₂CH₃, CH₂C(═O)OCH₂CH₃, OCH₃, CH₂C(═O)OH,OC(═O)CH₂CH₂C(═O)OCH₃, CH₂CH₂C(═O)OCH₃, C(═O)CH₃, C(═O)OCH₂-phenyl,C(═O)CH₂CH₂C(═O)OCH₃, C(═O)CH₂CH₂C(═O)OH, F, phenyl, CH₂C(═O)OCH₃,S(═O)₂CH₃, OCH₂-phenyl, CH₂-phenyl, C(═O)NH₂, CHO, —NH₂, NHC(═O)CH₃,C(═O)N(CH₃)₂, NHS(═O)₂CH₃, —CF₃, 3-methyl-[1,2,4]oxadiazol-5-yl, andCH(CH₃)₂.

In some embodiments, R₄ is selected from the group consisting ofpyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl,piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridin-3-yl,pyridin-2-yl, pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl,morpholin-2-yl, 2,5-diaza-bicyclo[2.2.1]hept-2-yl, [1,4]oxazepan-4-yl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, piperidin-2-yl, azepan-1-yl,pyrrolidin-3-yl, 3-oxo-piperazin-1-yl, 7-aza-bicyclo[2.2.1]hept-7-yl,and imidazol-1-yl each optionally substituted with substituents selectedindependently from the group consisting of CH₃, C(═O)O-t-butyl, C(═O)OH,C(═O)OEt, NHC(═O)O-t-butyl, OH, C(═O)NHCH₂C(═O)OCH₃,NHC(═O)CH₂C(═O)OCH₃, C(═O)NHCH₂C(═O)OH, NHC(═O)CH₂C(═O)OH, C(═O)OCH₃,OC(═O)CH₂CH₂C(═O)OCH₃, OC(═O)CH₂CH₂CH₂CH₂CH₃, CH₂C(═O)OCH₂CH₃, OCH₃,CH₂C(═O)OH, OC(═O)CH₂CH₂C(═O)OCH₃, CH₂CH₂C(═O)OCH₃, C(═O)CH₃, andC(═O)OCH₂-phenyl, C(═O)CH₂CH₂C(═O)OCH₃, C(═O)CH₂CH₂C(═O)OH, F, phenyl,CH₂C(═O)OCH₃, S(═O)₂CH₃, OCH₂-phenyl, CH₂-phenyl, C(═O)NH₂, CHO, —NH₂,NHC(═O)CH₃, C(═O)N(CH₃)₂, NHS(═O)₂CH₃, —CF₃,3-methyl-[1,2,4]oxadiazol-5-yl, and CH(CH₃)₂.

In some embodiments, R₄ is selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl,azetidinyl, thiomorpholinyl and 2,5-diaza-bicyclo[2.2.1]heptyloptionally substituted with substituents selected independently from thegroup consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₆ alkyl,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy,carboxy, and hydroxyl; wherein C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, and carbo-C₁₋₆-alkoxy are each optionally substitutedwith carbo-C₁₋₆-alkoxy, carboxy, and phenyl.

In some embodiments, R₄ is selected from the group consisting ofpyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl,azetidinyl, thiomorpholinyl and 2,5-diaza-bicyclo[2.2.1]heptyloptionally substituted with substituents selected independently from thegroup consisting of CH₃, C(═O)O-t-butyl, C(═O)OH, C(═O)O Et,NHC(═O)O-t-butyl, OH, C(═O)NHCH₂C(═O)OCH₃, NHC(═O)CH₂C(═O)OCH₃,C(═O)NHCH₂C(═O)OH, NHC(═O)CH₂C(═O)OH, C(═O)OCH₃, OC(═O)CH₂CH₂C(═O)OCH₃,OC(═O)CH₂CH₂CH₂CH₂CH₃, CH₂C(═O)OCH₂CH₃, OCH₃, CH₂C(═O)OH,OC(═O)CH₂CH₂C(═O)OCH₃, CH₂CH₂C(═O)OCH₃, C(═O)CH₃, and C(═O)OCH₂-phenyl.

In some embodiments, R₄ is selected from the group consisting ofpyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl,piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridin-3-yl,pyridin-2-yl, pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl and2,5-diaza-bicyclo[2.2.1]heptyl optionally substituted with substituentsselected independently from the group consisting of CH₃, C(═O)O-t-butyl,C(═O)OH, C(═O)OEt, NHC(═O)O-t-butyl, OH, C(═O)NHCH₂C(═O)OCH₃,NHC(═O)CH₂C(═O)OCH₃, C(═O)NHCH₂C(═O)OH, NHC(═O)CH₂C(═O)OH, C(═O)OCH₃,OC(═O)CH₂CH₂C(═O)OCH₃, OC(═O)CH₂CH₂CH₂CH₂CH₃, CH₂C(═O)OCH₂CH₃, OCH₃,CH₂C(═O)OH, OC(═O)CH₂CH₂C(═O)OCH₃, CH₂CH₂C(═O)OCH₃, C(═O)CH₃, andC(═O)OCH₂-phenyl.

In some embodiments, R₄ is selected from the group consisting ofmorpholin-4-yl, piperazin-1-yl, and 7-aza-bicyclo[2.2.1]hept-7-yl, andthe piperazin-1-yl is substituted with either C(═O)CH₃ or C(═O)NH₂.

In some embodiments, R₄ is 4-acetyl-piperazin-1-yl, morpholin-4-yl,piperidin-4-yl or pyrrolidin-1-yl.

In some embodiments, R₅, R₆, and R₇ are all H.

In some embodiments, R₅ is H.

In some embodiments, R₆ is H.

In some embodiments, R₇ is H.

In some embodiments, R₈ is C₁₋₈ alkyl, C₂₋₆ alkenyl, aryl, C₃₋₇cycloalkyl, or heteroaryl each optionally substituted with substituentsselected independently from the group consisting of C₁₋₆ acyl, C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, amino, C₁₋₆ alkylamino, C₂₋₈dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, heterocyclic,hydroxyl, nitro, and phenyl, or two adjacent substituents together withthe aryl or heteroaryl form a C₅₋₇ cycloalkyl optionally comprising 1 to2 oxygen atoms and optionally substituted with F.

In some embodiments, R₈ is C₁₋₈ alkyl, C₂₋₆ alkenyl, aryl or heteroaryleach optionally substituted with substituents selected independentlyfrom the group consisting of C₁₋₆ acyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆alkylsulfonyl, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₆alkylimino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, heterocyclic,hydroxyl, nitro, and phenyl, or two adjacent substituents together withthe aryl or heteroaryl form a C₅₋₇ cycloalkyl optionally comprising 1 to2 oxygen atoms and optionally substituted with F.

In some embodiments, R₈ is C₁₋₈ alkyl, C₂₋₆ alkenyl, aryl, C₃₋₇cycloalkyl, or heteroaryl each optionally substituted with substituentsselected independently from the group consisting of C₁₋₆ acyl, C₁₋₆alkoxy, C₁₋₆ alkyl, cyano, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, andhydroxyl, or two adjacent substituents together with the aryl orheteroaryl form a C₅₋₇ cycloalkyl optionally comprising 1 to 2 oxygenatoms and optionally substituted with F.

In some embodiments, R₈ is C₁₋₈ alkyl, C₂₋₆ alkenyl, aryl or heteroaryleach optionally substituted with substituents selected independentlyfrom the group consisting of C₁₋₆ acyl, C₁₋₆ alkoxy, C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, and hydroxyl, or two adjacent substituentstogether with the aryl or heteroaryl form a C₅₋₇ cycloalkyl optionallycomprising 1 to 2 oxygen atoms and optionally substituted with F.

In some embodiments, R₈ is C₁₋₈ alkyl, C₂₋₆ alkenyl, aryl, C₃₋₇cycloalkyl, or heteroaryl each optionally substituted with substituentsselected independently from the group consisting of C(═O)CH₃, OCH₃, CH₃,F, Cl, Br, CF₃, hydroxyl, OCF₃, and CN, or two adjacent substituentstogether with the aryl or heteroaryl form a C₅₋₇ cycloalkyl optionallycomprising 1 to 2 oxygen atoms and optionally substituted with F.

In some embodiments, R₈ is C₁₋₈ alkyl, C₂₋₆ alkenyl, aryl or heteroaryleach optionally substituted with substituents selected independentlyfrom the group consisting of C(═O)CH₃, OCH₃, CH₃, F, Cl, Br, CF₃ andhydroxyl, or two adjacent substituents together with the aryl orheteroaryl form a C₅₋₇ cycloalkyl optionally comprising 1 to 2 oxygenatoms and optionally substituted with F.

In some embodiments, R₈ is selected from the group consisting of methyl,iso-propyl, iso-butyl, n-propyl, n-butyl, 2-methyl-propenyl,3-methyl-butyl, phenyl, napthalenyl, cyclopropyl, cyclobutyl,cyclopentyl, pyridinyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl,thienyl, furanyl, benzothienyl, thiazolyl, isoxazolyl, and pyridin-4-yleach optionally substituted with substituents selected independentlyfrom the group consisting of C(═O)CH₃, OCH₃, CH₃, F, Cl, Br, CF₃,hydroxyl, OCF₃, and CN, or two adjacent substituents together with thephenyl form a C₅ cycloalkyl comprising 2 oxygen atoms and optionallysubstituted with F.

In some embodiments, R₈ is selected from the group consisting of methyl,iso-propyl, iso-butyl, n-propyl, n-butyl, 2-methyl-propenyl, phenyl,pyridinyl, benzoimidazolyl, benzooxazolyl and benzothiazolyl eachoptionally substituted with substituents selected independently from thegroup consisting of C(═O)CH₃, OCH₃, CH₃, F, Cl, Br, CF₃ and hydroxyl, ortwo adjacent substituents together with the phenyl form a C₅ cycloalkylcomprising 2 oxygen atoms and optionally substituted with F.

In some embodiments, R₈ is selected from the group consisting of methyl,iso-propyl, iso-butyl, n-propyl, n-butyl, 2-methyl-propenyl, phenyl,naphthalen-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, pyridin-2-yl,pyridin-3-yl, 1H-benzoimidazol-2-yl, benzooxazol-2-yl,benzothiazol-2-yl, thiophen-2-yl, furan-2-yl, benzothiophen-2-yl,thiazol-2-yl, isoxazol-3-yl, and pyridin-4-yl each optionallysubstituted with substituents selected independently from the groupconsisting of C(═O)CH₃, OCH₃, CH₃, F, Cl, Br, CF₃, hydroxyl, OCF₃, andCN, or two adjacent substituents together with the phenyl form a C₅cycloalkyl comprising 2 oxygen atoms and optionally substituted with F.

In some embodiments, R₈ is selected from the group consisting of methyl,iso-propyl, iso-butyl, n-propyl, n-butyl, 2-methyl-propenyl, phenyl,pyridin-2-yl, pyridin-3-yl, 1H-benzoimidazol-2-yl, benzooxazol-2-yl andbenzothiazol-2-yl, each optionally substituted with substituentsselected independently from the group consisting of C(═O)CH₃, OCH₃, CH₃,F, Cl, Br, CF₃ and hydroxyl, or two adjacent substituents together withthe phenyl form a C₅ cycloalkyl comprising 2 oxygen atoms and optionallysubstituted with F.

In some embodiments, R₈ is selected from the group consisting of4-chloro-phenyl, 2,4-difluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl,2,2-difluoro-benzo[1,3]dioxol-5-yl, 4-hydroxy-phenyl,4-chloro-2-hydroxy-phenyl, phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl,2-chloro-phenyl, 4-bromo-phenyl, 4-methoxy-phenyl,4-trifluoromethyl-phenyl, 3,5-bis-trifluoromethyl-phenyl,2-fluoro-5-methyl-phenyl, 3-methoxy-phenyl, 3-acetyl-phenyl,4-methyl-phenyl, 3-trifluoromethyl-phenyl, 3,5-difluoro-phenyl,2,4-dichloro-phenyl, 4-chloro-2-trifluoromethyl-phenyl,3,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl,naphthalen-1-yl, 4-trifluoromethoxy-phenyl, 3-cyano-phenyl,2-trifluoromethoxy-phenyl, 4-chloro-2-fluoro-phenyl,2,3-difluoro-phenyl, 2,4,5-trifluoro-phenyl, 2,3,4-trifluoro-phenyl,3,4-dichloro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl,5-fluoro-2-trifluoromethyl-phenyl, 2-trifluoromethyl-phenyl,3-methyl-phenyl, 2-fluoro-4-trifluoromethyl-phenyl,4-chloro-3-fluoro-phenyl, 3-fluoro-4-methyl-phenyl,4-fluoro-3-methyl-phenyl, 3-fluoro-4-trifluoromethyl-phenyl,3-chloro-4-fluoro-phenyl, 2,6-dichloro-phenyl, 4-cyano-phenyl, and2,5-dichloro-phenyl.

In some embodiments, R₈ is selected from the group consisting of4-chloro-phenyl, 2,4-difluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl,2,2-difluoro-benzo[1,3]dioxol-5-yl, 4-hydroxy-phenyl,4-chloro-2-hydroxy-phenyl, phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl,2-chloro-phenyl, 4-bromo-phenyl, 4-methoxy-phenyl,4-trifluoromethyl-phenyl, 3,5-bis-trifluoromethyl-phenyl,2-fluoro-5-methyl-phenyl, 3-methoxy-phenyl, 3-acetyl-phenyl,4-methyl-phenyl, 3-trifluoromethyl-phenyl, 3,5-difluoro-phenyl,2,4-dichloro-phenyl, 4-chloro-2-trifluoromethyl-phenyl,3,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl,naphthalen-1-yl, 4-trifluoromethoxy-phenyl, 3-cyano-phenyl,2-trifluoromethoxy-phenyl, 4-chloro-2-fluoro-phenyl,2,3-difluoro-phenyl, 2,4,5-trifluoro-phenyl, 2,3,4-trifluoro-phenyl,3,4-dichloro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl,5-fluoro-2-trifluoromethyl-phenyl, 2-trifluoromethyl-phenyl,3-methyl-phenyl, 2-fluoro-4-trifluoromethyl-phenyl,4-chloro-3-fluoro-phenyl, 3-fluoro-4-methyl-phenyl,4-fluoro-3-methyl-phenyl, 3-fluoro-4-trifluoromethyl-phenyl,3-chloro-4-fluoro-phenyl, 2,6-dichloro-phenyl, 4-cyano-phenyl,2,5-dichloro-phenyl, and benzo[1,3]dioxol-5-yl.

In some embodiments, R₈ is selected from the group consisting of4-chloro-phenyl, 2,4-difluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl,2,2-difluoro-benzo[1,3]dioxol-5-yl, 4-hydroxy-phenyl,4-chloro-2-hydroxy-phenyl, phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl,2-chloro-phenyl, 4-bromo-phenyl, 4-methoxy-phenyl,4-trifluoromethyl-phenyl, 3,5-bis-trifluoromethyl-phenyl,2-fluoro-5-methyl-phenyl, 3-methoxy-phenyl, 3-acetyl-phenyl,4-methyl-phenyl and 3-trifluoromethyl-phenyl.

In some embodiments, R₈ is selected from the group consisting of methyl,iso-propyl, iso-butyl, n-propyl, n-butyl, 2-methyl-propenyl,3-methyl-butyl, cyclopropyl, cyclobutyl, and cyclopentyl.

In some embodiments, R₈ is selected from the group consisting of methyl,iso-propyl, iso-butyl, n-propyl, n-butyl, and 2-methyl-propenyl.

In some embodiments, R₈ is a 5-membered heteroaryl is selected from thegroup shown in TABLE 1.

In some embodiments, R₈ is a 6-membered heteroaryl is selected from thegroup shown in TABLE 2.

In some embodiments, R₈ is selected from the group consisting ofpyridin-3-yl, 6-trifluoromethyl-pyridin-3-yl, 3-hydroxy-pyridin-2-yl,6-methyl-pyridin-3-yl, 6-hydroxy-pyridin-3-yl, 1H-benzoimidazol-2-yl,benzooxazol-2-yl, benzothiazol-2-yl, thiophen-2-yl, furan-2-yl,5-chloro-thiophen-2-yl, benzothiophen-2-yl, thiazol-2-yl,5-methyl-isoxazol-3-yl, and pyridin-4-yl.

In some embodiments, R₈ is selected from the group consisting ofpyridin-3-yl, 6-trifluoromethyl-pyridin-3-yl, 3-hydroxy-pyridin-2-yl,6-methyl-pyridin-3-yl, 6-hydroxy-pyridin-3-yl, 1H-benzoimidazol-2-yl,benzooxazol-2-yl and benzothiazol-2-yl.

In some embodiments, R₉ is H.

In some embodiments, R₉ is C₁₋₈ alkyl.

In some embodiments, R₁₀ is H.

In some embodiments, R₁₀ is C₁₋₈ alkyl.

In some embodiments, R₁₁ is H.

In some embodiments, R₁₁ is C₁₋₈ alkyl.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Ik):

or a pharmaceutically acceptable salt thereof;

wherein:

W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)—, —CH₂CH₂CH₂—, —C(CH₃)₂C(═O)—,—CH₂CH(CH₃)—, —CH(CH₃)CH₂—, —C(CH₃)₂CH₂—, or —CH₂C(CH₃)₂—; or W isabsent;

X is C(═O) or absent;

Y is NH, O or absent;

Z is absent, —CH₂—, —CH(OH)—, —CF₂—, —C(CH₃)₂—, 1,1-cyclopropyl,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—, or —C(═O)—;

R₁ is C₁₋₆ alkyl;

R₃ is H or halogen;

R₄ is heterobicyclic, heterocyclic, or heteroaryl, each optionallysubstituted with substituents selected independently from the groupconsisting of C₁₋₆ acyl, C₁₋₁₂ acyloxy, C₁₋₄ alkoxy, C₁₋₆alkoxycarbonylamino, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, C₂₋₆ dialkylcarboxamide,formyl, halogen, C₁₋₄ haloalkyl, heteroaryl, hydroxyl and phenyl;wherein said C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₄alkylcarboxamide, amino, carbo-C₁₋₆-alkoxy and heteroaryl are eachoptionally substituted with substituents selected independently from thegroup consisting of C₁₋₆ alkyl, carbo-C₁₋₆-alkoxy, carboxy, and phenyl;and

R₈ is C₁₋₈ alkyl, C₂₋₆ alkenyl, aryl, C₃₋₇ cycloalkyl, or heteroaryl,each optionally substituted with substituents selected independentlyfrom the group consisting of C₁₋₆ acyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆alkylsulfonyl, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₆alkylimino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, heterocyclic,hydroxyl, nitro, and phenyl, or two adjacent substituents together withthe aryl or heteroaryl form a C₅₋₇ cycloalkyl optionally comprising 1 to2 oxygen atoms and optionally substituted with F.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Ik), supra, or apharmaceutically acceptable salt thereof;

wherein:

W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)—, —CH₂CH₂CH₂— or W is absent;

X is C(═O) or absent;

Y is NH, O or absent;

Z is —CH₂—, —CH(OH)— or absent;

R₁ is C₁₋₆ alkyl;

R₃ is H or halogen;

R₄ is heterocyclic or heteroaryl, each optionally substituted withsubstituents selected independently from the group consisting of C₁₋₆acyl, C₁₋₁₂ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₆ alkylamino, C_(2-g)dialkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆cycloalkyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, and hydroxyl;wherein C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, andcarbo-C₁₋₆-alkoxy are each optionally substituted with C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, andphenyl; and

R₈ is C₁₋₈ alkyl, C₂₋₆ alkenyl, aryl or heteroaryl, each optionallysubstituted with substituents selected independently from the groupconsisting of C₁₋₆ acyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl,amino, C₁₋₆ alkylamino, C_(2-g) dialkylamino, C₁₋₆ alkylimino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, heterocyclic, hydroxyl, nitro,and phenyl, or two adjacent substituents together with the aryl orheteroaryl form a C₅₋₇ cycloalkyl optionally comprising 1 to 2 oxygenatoms and optionally substituted with F.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Ik), supra, or apharmaceutically acceptable salt thereof;

wherein:

W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)—, —CH₂CH₂CH₂—, —C(CH₃)₂C(═O)—,—CH₂CH(CH₃)—, —CH(CH₃)CH₂—, —C(CH₃)₂CH₂—, or —CH₂C(CH₃)₂—; or W isabsent;

X is C(═O) or absent;

Y is NH, O or absent;

Z is absent, —CH₂—, —CH(OH)—, —CF₂—, —C(CH₃)₂—, 1,1-cyclopropyl,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—, or —C(═O)—;

R₁ is C₁₋₆ alkyl;

R₃ is H or halogen;

R₄ is heterobicyclic, heterocyclic, or heteroaryl, each optionallysubstituted with substituents selected independently from the groupconsisting of C₁₋₆ acyl, C₁₋₁₂ acyloxy, C₁₋₄ alkoxy, C₁₋₆alkoxycarbonylamino, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, C₂₋₆ dialkylcarboxamide,formyl, halogen, C₁₋₄ haloalkyl, heteroaryl, hydroxyl and phenyl;wherein said C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₄alkylcarboxamide, amino, carbo-C₁₋₆-alkoxy and heteroaryl are eachoptionally substituted with substituents selected independently from thegroup consisting of C₁₋₆ alkyl, carbo-C₁₋₆-alkoxy, carboxy, and phenyl;and

R₈ is selected from the group consisting of 4-chloro-phenyl,2,4-difluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl,2,2-difluoro-benzo[1,3]dioxol-5-yl, 4-hydroxy-phenyl,4-chloro-2-hydroxy-phenyl, phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl,2-chloro-phenyl, 4-bromo-phenyl, 4-methoxy-phenyl,4-trifluoromethyl-phenyl, 3,5-bis-trifluoromethyl-phenyl,2-fluoro-5-methyl-phenyl, 3-methoxy-phenyl, 3-acetyl-phenyl,4-methyl-phenyl, 3-trifluoromethyl-phenyl, 3,5-difluoro-phenyl,2,4-dichloro-phenyl, 4-chloro-2-trifluoromethyl-phenyl,3,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl,naphthalen-1-yl, 4-trifluoromethoxy-phenyl, 3-cyano-phenyl,2-trifluoromethoxy-phenyl, 4-chloro-2-fluoro-phenyl,2,3-difluoro-phenyl, 2,4,5-trifluoro-phenyl, 2,3,4-trifluoro-phenyl,3,4-dichloro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl,5-fluoro-2-trifluoromethyl-phenyl, 2-trifluoromethyl-phenyl,3-methyl-phenyl, 2-fluoro-4-trifluoromethyl-phenyl,4-chloro-3-fluoro-phenyl, 3-fluoro-4-methyl-phenyl,4-fluoro-3-methyl-phenyl, 3-fluoro-4-trifluoromethyl-phenyl,3-chloro-4-fluoro-phenyl, 2,6-dichloro-phenyl, 4-cyano-phenyl,2,5-dichloro-phenyl, and benzo[1,3]dioxol-5-yl.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Im):

or a pharmaceutically acceptable salt thereof;

wherein:

W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)—, —CH₂CH₂CH₂—, —C(CH₃)₂C(═O)—,—CH₂CH(CH₃)—, —CH(CH₃)CH₂—, —C(CH₃)₂CH₂—, or —CH₂C(CH₃)₂—; or W isabsent;

Y is NH, O or absent;

Z is absent, —CH₂—, —CH(OH)—, —CF₂—, —C(CH₃)₂—, 1,1-cyclopropyl,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—, or —C(═O)—;

R₁ is C₁₋₆ alkyl;

R₃ is H or halogen;

R₄ is selected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, pyridinyl, azetidinyl, thiomorpholinyl2,5-diaza-bicyclo[2.2.1]heptyl, [1,4]oxazepanyl,1,1-dioxo-1λ⁶-thiomorpholinyl, azepanyl, and 3-oxo-piperazinyl,aza-bicyclo[2.2.1]heptyl, and imidazolyl, each optionally substitutedwith substituents selected independently from the group consisting ofC₁₋₆ acyl, C₁₋₁₂ acyloxy, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, C₂₋₆dialkylcarboxamide, formyl, halogen, C₁₋₄ haloalkyl, heteroaryl,hydroxyl and phenyl; wherein said C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy,C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, amino, carbo-C₁₋₆-alkoxy andheteroaryl are each optionally substituted with substituents selectedindependently from the group consisting of C₁₋₆ alkyl,carbo-C₁₋₆-alkoxy, carboxy, and phenyl; and

R₈ is selected from the group consisting of methyl, iso-propyl,iso-butyl, n-propyl, n-butyl, 2-methyl-propenyl, 3-methyl-butyl, phenyl,napthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, pyridinyl,benzoimidazolyl, benzooxazolyl, benzothiazolyl, thienyl, furanyl,benzothienyl, thiazolyl, isoxazolyl, and pyridin-4-yl, each optionallysubstituted with substituents selected independently from the groupconsisting of C(═O)CH₃, OCH₃, CH₃, F, Cl, Br, CF₃, hydroxyl, OCF₃, andCN, or two adjacent substituents together with the phenyl form a C₅cycloalkyl comprising 2 oxygen atoms and optionally substituted with F.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Im), supra, or apharmaceutically acceptable salt thereof;

wherein:

W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)—, —CH₂CH₂CH₂— or W is absent;

Y is NH, O or absent;

Z is absent, —CH₂— or —CH(OH)—;

R₁ is C₁₋₆ alkyl;

R₃ is H or halogen;

R₄ is selected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, pyridinyl, azetidinyl, thiomorpholinyl and2,5-diaza-bicyclo[2.2.1]heptyl, optionally substituted with substituentsselected independently from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxy, and hydroxyl; whereinC₁₋₅ acyl, C₁₋₅ acyloxy, C_(1-g) alkyl, C₁₋₄ alkylcarboxamide, andcarbo-C₁₋₆-alkoxy are each optionally substituted withcarbo-C₁₋₆-alkoxy, carboxy, and phenyl; and

R₈ is selected from the group consisting of methyl, iso-propyl,iso-butyl, n-propyl, n-butyl, 2-methyl-propenyl, phenyl, pyridin-2-yl,pyridin-3-yl, 1H-benzoimidazol-2-yl, benzooxazol-2-yl andbenzothiazol-2-yl, each optionally substituted with substituentsselected independently from the group consisting of C(═O)CH₃, OCH₃, CH₃,F, Cl, Br, CF₃ and hydroxyl, or two adjacent substituents together withthe phenyl form a C₅ cycloalkyl comprising 2 oxygen atoms and optionallysubstituted with F.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Im), supra, or apharmaceutically acceptable salt thereof;

wherein:

W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)—, —CH₂CH₂CH₂—, —C(CH₃)₂C(═O)—,—CH₂CH(CH₃), —CH(CH₃)CH₂—, —C(CH₃)₂CH₂—, or —CH₂C(CH₃)₂—; or W isabsent;

Y is NH, O or absent;

Z is absent, —CH₂—, —CH(OH)—, —CF₂—, —C(CH₃)₂—, 1,1-cyclopropyl,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—, or —C(═O)—;

R₁ is C₁₋₆ alkyl;

R₃ is H or halogen;

R₄ is selected from the group consisting of pyrrolidin-1-yl,pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl,morpholin-4-yl, piperazin-1-yl, pyridin-3-yl, pyridin-2-yl,pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl, morpholin-2-yl,2,5-diaza-bicyclo[2.2.1]hept-2-yl, [1,4]oxazepan-4-yl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, piperidin-2-yl, azepan-1-yl,pyrrolidin-3-yl, 3-oxo-piperazin-1-yl, 7-aza-bicyclo[2.2.1]hept-7-yl,and imidazol-1-yl, each optionally substituted with substituentsselected independently from the group consisting of CH₃, C(═O)O-t-butyl,C(═O)OH, C(═O)OEt, NHC(═O)O-t-butyl, OH, C(═O)NHCH₂C(═O)OCH₃,NHC(═O)CH₂C(═O)OCH₃, C(═O)NHCH₂C(═O)OH, NHC(═O)CH₂C(═O)OH, C(═O)OCH₃,OC(═O)CH₂CH₂C(═O)OCH₃, OC(═O)CH₂CH₂CH₂CH₂CH₃, CH₂C(═O)OCH₂CH₃, OCH₃,CH₂C(═O)OH, OC(═O)CH₂CH₂C(═O)OCH₃, CH₂CH₂C(═O)OCH₃, C(═O)CH₃, andC(═O)OCH₂-phenyl, C(═O)CH₂CH₂C(═O)OCH₃, C(═O)CH₂CH₂C(═O)OH, F, phenyl,CH₂C(═O)OCH₃, S(═O)₂CH₃, OCH₂-phenyl, CH₂-phenyl, C(═O)NH₂, CHO, —NH₂,NHC(═O)CH₃, C(═O)N(CH₃)₂, NHS(═O)₂CH₃, —CF₃,3-methyl-[1,2,4]oxadiazol-5-yl, and CH(CH₃)₂; and

R₈ is selected from the group consisting of 4-chloro-phenyl,2,4-difluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl,2,2-difluoro-benzo[1,3]dioxol-5-yl, 4-hydroxy-phenyl,4-chloro-2-hydroxy-phenyl, phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl,2-chloro-phenyl, 4-bromo-phenyl, 4-methoxy-phenyl,4-trifluoromethyl-phenyl, 3,5-bis-trifluoromethyl-phenyl,2-fluoro-5-methyl-phenyl, 3-methoxy-phenyl, 3-acetyl-phenyl,4-methyl-phenyl, 3-trifluoromethyl-phenyl, 3,5-difluoro-phenyl,2,4-dichloro-phenyl, 4-chloro-2-trifluoromethyl-phenyl,3,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl,naphthalen-1-yl, 4-trifluoromethoxy-phenyl, 3-cyano-phenyl,2-trifluoromethoxy-phenyl, 4-chloro-2-fluoro-phenyl,2,3-difluoro-phenyl, 2,4,5-trifluoro-phenyl, 2,3,4-trifluoro-phenyl,3,4-dichloro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl,5-fluoro-2-trifluoromethyl-phenyl, 2-trifluoromethyl-phenyl,3-methyl-phenyl, 2-fluoro-4-trifluoromethyl-phenyl,4-chloro-3-fluoro-phenyl, 3-fluoro-4-methyl-phenyl,4-fluoro-3-methyl-phenyl, 3-fluoro-4-trifluoromethyl-phenyl,3-chloro-4-fluoro-phenyl, 2,6-dichloro-phenyl, 4-cyano-phenyl, and2,5-dichloro-phenyl.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Im), supra, or apharmaceutically acceptable salt thereof;

wherein:

W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)—, —CH₂CH₂CH₂— or W is absent;

Y is NH, O or absent;

Z is absent, —CH₂— or —CH(OH)—;

R₁ is C₁₋₆ alkyl;

R₃ is H or halogen;

R₄ is selected from the group consisting of pyrrolidin-1-yl,pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl,morpholin-4-yl, piperazin-1-yl, pyridin-3-yl, pyridin-2-yl,pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl and2,5-diaza-bicyclo[2.2.1]heptyl, each optionally substituted withsubstituents selected independently from the group consisting of CH₃,C(═O)O-t-butyl, C(═O)OH, C(═O)OEt, NHC(═O)O-t-butyl, OH,C(═O)NHCH₂C(═O)OCH₃, NHC(═O)CH₂C(═O)OCH₃, C(═O)NHCH₂C(═O)OH,NHC(═O)CH₂C(═O)OH, C(═O)OCH₃, OC(═O)CH₂CH₂C(═O)OCH₃,OC(═O)CH₂CH₂CH₂CH₂CH₃, CH₂C(═O)OCH₂CH₃, OCH₃, CH₂C(═O)OH,OC(═O)CH₂CH₂C(═O)OCH₃, CH₂CH₂C(═O)OCH₃, C(═O)CH₃, and C(═O)OCH₂-phenyl;and

R₈ is selected from the group consisting of 4-chloro-phenyl,2,4-difluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl,2,2-difluoro-benzo[1,3]dioxol-5-yl, 4-hydroxy-phenyl,4-chloro-2-hydroxy-phenyl, phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl,2-chloro-phenyl, 4-bromo-phenyl, 4-methoxy-phenyl,4-trifluoromethyl-phenyl, 3,5-bis-trifluoromethyl-phenyl,2-fluoro-5-methyl-phenyl, 3-methoxy-phenyl, 3-acetyl-phenyl,4-methyl-phenyl and 3-trifluoromethyl-phenyl.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Im), supra, or apharmaceutically acceptable salt thereof;

wherein:

W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)—, —CH₂CH₂CH₂—, —C(CH₃)₂C(═O)—,—CH₂CH(CH₃), —CH(CH₃)CH₂—, —C(CH₃)₂CH₂—, or —CH₂C(CH₃)₂—; or W isabsent;

Y is NH, O or absent;

Z is absent, —CH₂—, —CH(OH)—, —CF₂—, —C(CH₃)₂—, 1,1-cyclopropyl,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—, or —C(═O)—;

R₁ is C₁₋₆ alkyl;

R₃ is H or halogen;

R₄ is selected from the group consisting of pyrrolidin-1-yl,pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl,morpholin-4-yl, piperazin-1-yl, pyridin-3-yl, pyridin-2-yl,pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl, morpholin-2-yl,2,5-diaza-bicyclo[2.2.1]hept-2-yl, [1,4]oxazepan-4-yl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, piperidin-2-yl, azepan-1-yl,pyrrolidin-3-yl, 3-oxo-piperazin-1-yl, 7-aza-bicyclo[2.2.1]hept-7-yl,and imidazol-1-yl, each optionally substituted with substituentsselected independently from the group consisting of CH₃, C(═O)O-t-butyl,C(═O)OH, C(═O)OEt, NHC(═O)O-t-butyl, OH, C(═O)NHCH₂C(═O)OCH₃,NHC(═O)CH₂C(═O)OCH₃, C(═O)NHCH₂C(═O)OH, NHC(═O)CH₂C(═O)OH, C(═O)OCH₃,OC(═O)CH₂CH₂C(═O)OCH₃, OC(═O)CH₂CH₂CH₂CH₂CH₃, CH₂C(═O)OCH₂CH₃, OCH₃,CH₂C(═O)OH, OC(═O)CH₂CH₂C(═O)OCH₃, CH₂CH₂C(═O)OCH₃, C(═O)CH₃, andC(═O)OCH₂-phenyl, C(═O)CH₂CH₂C(═O)OCH₃, C(═O)CH₂CH₂C(═O)OH, F, phenyl,CH₂C(═O)OCH₃, S(═O)₂CH₃, OCH₂-phenyl, CH₂-phenyl, C(═O)NH₂, CHO, —NH₂,NHC(═O)CH₃, C(═O)N(CH₃)₂, NHS(═O)₂CH₃, —CF₃,3-methyl-[1,2,4]oxadiazol-5-yl, and CH(CH₃)₂; and

R₈ is selected from the group consisting of methyl, iso-propyl,iso-butyl, n-propyl, n-butyl, 2-methyl-propenyl, 3-methyl-butyl,cyclopropyl, cyclobutyl, and cyclopentyl.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Im), supra, or apharmaceutically acceptable salt thereof;

wherein:

W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)—, —CH₂CH₂CH₂— or W is absent;

Y is NH, O or absent;

Z is absent, —CH₂— or —CH(OH)—;

R₁ is C₁₋₆ alkyl;

R₃ is H or halogen;

R₄ is selected from the group consisting of pyrrolidin-1-yl,pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl,morpholin-4-yl, piperazin-1-yl, pyridin-3-yl, pyridin-2-yl,pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl and2,5-diaza-bicyclo[2.2.1]heptyl, each optionally substituted withsubstituents selected independently from the group consisting of CH₃,C(═O)O-t-butyl, C(═O)OH, C(═O)OEt, NHC(═O)O-t-butyl, OH,C(═O)NHCH₂C(═O)OCH₃, NHC(═O)CH₂C(═O)OCH₃, C(═O)NHCH₂C(═O)OH,NHC(═O)CH₂C(═O)OH, C(═O)OCH₃, OC(═O)CH₂CH₂C(═O)OCH₃,OC(═O)CH₂CH₂CH₂CH₂CH₃, CH₂C(═O)OCH₂CH₃, OCH₃, CH₂C(═O)OH,OC(═O)CH₂CH₂C(═O)OCH₃, CH₂CH₂C(═O)OCH₃, C(═O)CH₃, and C(═O)OCH₂-phenyl;and

R₈ is selected from the group consisting of methyl, iso-propyl,iso-butyl, n-propyl, n-butyl, and 2-methyl-propenyl.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Im), supra, or apharmaceutically acceptable salt thereof;

wherein:

W is —CH₂CH₂—; Y is NH or absent; R₁ is CH₃; R₄ is4-acetyl-piperazin-1-yl, morpholin-4-yl, piperidin-4-yl orpyrrolidin-1-yl; and

R₈ is phenyl or C₃₋₇ cycloalkyl, each optionally substituted with 1, 2,or 3 substituents selected independently from the group consisting ofC(═O)CH₃, OCH₃, CH₃, F, Cl, Br, CF₃ and hydroxyl.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Ik), supra, or apharmaceutically acceptable salt thereof;

wherein:

W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)—, —CH₂CH₂CH₂—, —C(CH₃)₂C(═O)—,—CH₂CH(CH₃), —CH(CH₃)CH₂—, —C(CH₃)₂CH₂—, or —CH₂C(CH₃)₂—; or W isabsent;

X is C(═O) or absent;

Y is NH, O or absent;

Z is absent, —CH₂—, —CH(OH)—, —CF₂—, —C(CH₃)₂—, 1,1-cyclopropyl,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—, or —C(═O)—;

R₁ is C₁₋₆ alkyl;

R₃ is H or halogen;

R₄ is selected from the group consisting of pyrrolidin-1-yl,pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl,morpholin-4-yl, piperazin-1-yl, pyridin-3-yl, pyridin-2-yl,pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl, morpholin-2-yl,2,5-diaza-bicyclo[2.2.1]hept-2-yl, [1,4]oxazepan-4-yl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, piperidin-2-yl, azepan-1-yl,pyrrolidin-3-yl, 3-oxo-piperazin-1-yl, 7-aza-bicyclo[2.2.1]hept-7-yl,and imidazol-1-yl, each optionally substituted with substituentsselected independently from the group consisting of CH₃, C(═O)O-t-butyl,C(═O)OH, C(═O)OEt, NHC(═O)O-t-butyl, OH, C(═O)NHCH₂C(═O)OCH₃,NHC(═O)CH₂C(═O)OCH₃, C(═O)NHCH₂C(═O)OH, NHC(═O)CH₂C(═O)OH, C(═O)OCH₃,OC(═O)CH₂CH₂C(═O)OCH₃, OC(═O)CH₂CH₂CH₂CH₂CH₃, CH₂C(═O)OCH₂CH₃, OCH₃,CH₂C(═O)OH, OC(═O)CH₂CH₂C(═O)OCH₃, CH₂CH₂C(═O)OCH₃, C(═O)CH₃, andC(═O)OCH₂-phenyl, C(═O)CH₂CH₂C(═O)OCH₃, C(═O)CH₂CH₂C(═O)OH, F, phenyl,CH₂C(═O)OCH₃, S(═O)₂CH₃, OCH₂-phenyl, CH₂-phenyl, C(═O)NH₂, CHO, —NH₂,NHC(═O)CH₃, C(═O)N(CH₃)₂, NHS(═O)₂CH₃, —CF₃,3-methyl-[1,2,4]oxadiazol-5-yl, and CH(CH₃)₂; and

R₈ is selected from the group consisting of pyridin-3-yl,6-trifluoromethyl-pyridin-3-yl, 3-hydroxy-pyridin-2-yl,6-methyl-pyridin-3-yl, 6-hydroxy-pyridin-3-yl, 1H-benzoimidazol-2-yl,benzooxazol-2-yl, benzothiazol-2-yl, thiophen-2-yl, furan-2-yl,5-chloro-thiophen-2-yl, benzothiophen-2-yl, thiazol-2-yl,5-methyl-isoxazol-3-yl, and pyridin-4-yl.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Ik), supra, or apharmaceutically acceptable salt thereof;

wherein:

W is —CH₂—, —CH₂CH₂—, —CH₂C(═O)—, —CH₂CH₂CH₂— or W is absent;

X is C(═O) or absent;

Y is NH, O or absent;

Z is absent, —CH₂— or —CH(OH)—;

R₁ is C₁₋₆ alkyl;

R₃ is H or halogen;

R₄ is pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl,piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridin-3-yl,pyridin-2-yl or pyridin-4-yl, each optionally substituted withsubstituents selected independently from the group consisting of CH₃,C(═O)O-t-butyl, C(═O)OH, C(═O)OEt, NHC(═O)O-t-butyl, OH,C(═O)NHCH₂C(═O)OCH₃, NHC(═O)CH₂C(═O)OCH₃, C(═O)NHCH₂C(═O)OH,NHC(═O)CH₂C(═O)OH, C(═O)OCH₃, OC(═O)CH₂CH₂C(═O)OCH₃,OC(═O)CH₂CH₂CH₂CH₂CH₃, CH₂C(═O)OCH₂CH₃, OCH₃, CH₂C(═O)OH,OC(═O)CH₂CH₂C(═O)OCH₃, CH₂CH₂C(═O)OCH₃, C(═O)CH₃, and C(═O)OCH₂-phenyl;and

R₈ is selected from the group consisting of pyridin-3-yl,6-trifluoromethyl-pyridin-3-yl, 3-hydroxy-pyridin-2-yl,6-methyl-pyridin-3-yl, 6-hydroxy-pyridin-3-yl, 1H-benzoimidazol-2-yl,benzooxazol-2-yl and benzothiazol-2-yl.

Some embodiments of the present invention encompass certain3-phenyl-pyrazole derivatives as shown in Formula (Io):

or a pharmaceutically acceptable salt thereof;

wherein:

W is —CH₂—, —CH₂CH₂— or —CH₂C(═O)—;

R₁ is C₁₋₆ alkyl;

R₃ is H or halogen;

R₄ is pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl,piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridin-3-yl,pyridin-2-yl or pyridin-4-yl, each optionally substituted withsubstituents selected independently from the group consisting of CH₃,C(═O)O-t-butyl, C(═O)OH, C(═O)OEt, NHC(═O)O-t-butyl, OH,C(═O)NHCH₂C(═O)OCH₃, NHC(═O)CH₂C(═O)OCH₃, C(═O)NHCH₂C(═O)OH,NHC(═O)CH₂C(═O)OH, C(═O)OCH₃, OC(═O)CH₂CH₂C(═O)OCH₃,OC(═O)CH₂CH₂CH₂CH₂CH₃, CH₂C(═O)OCH₂CH₃, OCH₃, CH₂C(═O)OH,OC(═O)CH₂CH₂C(═O)OCH₃, CH₂CH₂C(═O)OCH₃, C(═O)CH₃, and C(═O)OCH₂-phenyl;and

R₈ is selected from the group consisting of 1H-benzoimidazol-2-yl,benzooxazol-2-yl and benzothiazol-2-yl.

Some embodiments of the present invention include every combination ofone or more compounds selected from the following group, where thenumber in bold directly preceding the chemical name refers to theCompound Number that is used elsewhere in this disclosure:

#1:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea;#2:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea;#3:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea;#4:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea;#5:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea;#6:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea;#7:[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-carbamicacid isopropyl ester; #8:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-urea;#9:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea;#10:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)-phenyl]-3-(4-chloro-phenyl)-urea;#11:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea;#12:[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-carbamicacid isopropyl ester; #13:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea;#14:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea;#15:1-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-3-(2,4-difluoro-phenyl)-urea;#16:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea;#17:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea;#18:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea;#19:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea;#20:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-acetamide;#21:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-fluoro-phenyl)-urea;#22:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(3-chloro-phenyl)-urea;#23:[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-carbamicacid isobutyl ester; #24:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-urea;#25:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-hydroxy-phenyl)-urea;#26:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-2-hydroxy-phenyl)-urea;#27:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea;#28:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(pyridin-2-ylmethoxy)-phenyl]-urea;#29:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(pyridin-3-ylmethoxy)-phenyl]-urea;#30:[3-(2-Methyl-2H-pyrazol-3-yl)-4-(pyridin-3-ylmethoxy)-phenyl]-carbamicacid isopropyl ester; #31:(R)-3-[4-[3-(2,4-Difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-1-carboxylic acid tert-butyl ester; #32:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetamide;#33:[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-carbamicacid isopropyl ester; #34:[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-carbamicacid isobutyl ester; #35:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-2-phenyl-acetamide;#36:4-[4-Acetylamino-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester; #37:(R)-3-[4-Isopropoxycarbonylamino-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-1-carboxylicacid tert-butyl ester; #38:(S)-3-[4-[3-(4-Fluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-1-carboxylicacid tert-butyl ester; #39:(S)-3-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-1-carboxylicacid tert-butyl ester; #40:(S)-2-[4-[3-(2,4-Difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester; #41:(S)-2-[4-[3-(4-Fluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester; #42:(R)-2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester; #43:2-(4-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetamide;#44:1-Benzyl-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#45:1-(4-Chloro-benzyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#46:1-(4-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#47:1-(3-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#48:4-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester; #49:4-[4-[3-(4-Fluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester; #50:4-[4-[3-(2,4-Difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-piperidine-1-carboxylicacid tert-butyl ester; #51:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(pyridin-4-ylmethoxy)-phenyl]-urea;#52:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)-phenyl]-urea;#53:1-(4-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)-phenyl]-urea;#54:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)-phenyl]-urea;#55:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-((S)-pyrrolidin-3-yloxy)-phenyl]-urea;#56:1-(4-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-((S)-pyrrolidin-3-yloxy)-phenyl]-urea;#57:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-((S)-pyrrolidin-3-yloxy)-phenyl]-urea;#58:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-((S)-1-pyrrolidin-2-ylmethoxy)-phenyl]-urea;#59:1-(4-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-((S)-1-pyrrolidin-2-ylmethoxy)-phenyl]-urea;#60:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-((R)-1-pyrrolidin-2-ylmethoxy)-phenyl]-urea;#61:(2R,4R)-4-[4-[3-(2,4-Difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester; #62:(2R,4R)-4-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester; #63:(2R,4R)-4-[4-[3-(2,4-Difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-2-carboxylicacid; #64:(2R,4R)-4-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-2-carboxylicacid; #65:1-(2-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#66:1-(3-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#67:1-(2-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#68:1-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-phenyl-urea;#69:1-(4-Bromo-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#70:1-(3,5-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#71:1-(4-Methoxy-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#72:1-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea;#73:1-(3,5-Bis-trifluoromethyl-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#74:1-(2-Fluoro-5-methyl-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#75:1-(3-Methoxy-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#76:1-(3-Acetyl-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#77:(2S,4S)-4-[4-[3-(2,4-Difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester; #78:(2S,4S)-4-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester; #79:(2S,4S)-4-[4-[3-(2,4-Difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-2-carboxylicacid; #80:1-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-p-tolyl-urea;#81:1-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea;#82:(2S,4S)-4-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-2-carboxylicacid; #83:1-[4-(2-Azetidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-fluoro-phenyl)-urea;#84:1-[4-(2-Azetidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-chloro-phenyl)-urea;#85:1-(4-Chloro-phenyl)-3-[4-(1-methyl-piperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#86:1-[4-(2-Azetidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,4-difluoro-phenyl)-urea;#87:1-[4-(2-Azetidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-urea;#88:1-(4-Chloro-phenyl)-3-[4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#89:4-[4-[2-(4-Chloro-phenyl)-acetylamino]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-piperidine-1-carboxylicacid tert-butyl ester; #90:4-[4-Isobutoxycarbonylamino-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-piperidine-1-carboxylicacid tert-butyl ester; #91:4-[4-Isopropoxycarbonylamino-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-piperidine-1-carboxylicacid tert-butyl ester; #92:[3-(2-Methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)-phenyl]-carbamicacid isopropyl ester; #93:2-(4-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)-phenyl]-acetamide;#94:[3-(2-Methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)-phenyl]-carbamicacid isobutyl ester; #95:2-(4-Chloro-phenyl)-2-hydroxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-acetamide;#96:3-Methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-butyramide;#97:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#98:1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-4-carboxylicacid ethyl ester; #99:(1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-yl)-carbamicacid tert-butyl ester; #100:1-(4-Chloro-phenyl)-3-[4-[2-((S)-3-hydroxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#101:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-urea;#102:1-(4-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-urea;#103:1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-4-carboxylicacid; #104:1-[4-[2-(4-Amino-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-chloro-phenyl)-urea;#105:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#106: 3-Methyl-but-2-enoic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide;#107:[(1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amino]-aceticacid methyl ester; #108:N-(1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-yl)-malonamicacid methyl ester; #109:[(1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amino]-aceticacid; #110:N-(1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-yl)-malonamicacid; #111:(S)-1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-3-carboxylicacid methyl ester; #112:1-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea;#113:[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-carbamicacid isopropyl ester; #114:(S)-1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-3-carboxylicacid; #115:1-(3-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-urea;#116:1-(3-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-urea;#117:2-(4-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#118:[((S)-1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-3-carbonyl)-amino]-aceticacid methyl ester; #119:[((S)-1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-3-carbonyl)-amino]-aceticacid; #120:1-(4-Chloro-phenyl)-3-[4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#121:1-(2-{2-(2-Methyl-2H-pyrazol-3-yl)-4-[(pyridine-3-carbonyl)-amino]-phenoxy}-ethyl)-piperidine-4-carboxylicacid ethyl ester; #122:1-{2-[4-(3-Methyl-butyrylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-4-carboxylicacid ethyl ester; #123:1-{2-[4-Butyrylamino-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-4-carboxylicacid ethyl ester; #124:1-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-pentanoylamino-phenoxy]-ethyl}-piperidine-4-carboxylicacid ethyl ester; #125:1-{2-[4-[3-(2,4-Difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid methyl ester; #126:1-{2-[4-[3-(2,4-Difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-2-carboxylicacid ethyl ester; #127:4-[4-[3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-piperidine-1-carboxylicacid tert-butyl ester; #128:1-(4-Chloro-phenyl)-3-[4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#129:1-(2,4-Difluoro-phenyl)-3-[4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#130:1-(4-Fluoro-phenyl)-3-[4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#131:1-(4-Chloro-benzyl)-3-[4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#132:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-urea;#133:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-urea;#134:1-(2-{2-(2-Methyl-2H-pyrazol-3-yl)-4-[(6-trifluoromethyl-pyridine-3-carbonyl)-amino]-phenoxy}-ethyl)-piperidine-4-carboxylicacid ethyl ester; #135: Succinic acid1-{2-[4-[3-(4-chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-ylester methyl ester; #136: Hexanoic acid1-{2-[4-[3-(4-chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-ylester; #137:1-(2,4-Difluoro-phenyl)-3-[3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-urea;#138:(1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-yl)-aceticacid ethyl ester; #139:1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)-phenyl]-urea;#140:1-(2,4-Difluoro-phenyl)-3-[4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#141:1-(4-Chloro-phenyl)-3-[4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#142:(1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-yl)-aceticacid; #143:1-(4-Chloro-phenyl)-3-[4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#1-(4:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-methyl-butyramide;#145:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyridin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea;#146:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea;#147:[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-carbamicacid isobutyl ester; #148: Succinic acid(S)-1-{2-[4-[3-(4-chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-3-ylester methyl ester; #149:1-(2,4-Difluoro-phenyl)-3-[4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#150:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-methyl-butyramide;#151:3-(1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-yl)-propionicacid methyl ester; #152:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-urea;#153:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-urea;#154:[3-(2-Methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-carbamicacid isopropyl ester; #155:[3-(2-Methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-carbamicacid isobutyl ester; #156:1-(4-Chloro-phenyl)-3-[4-[2-(3-hydroxy-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#157:(1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-3-yl)-aceticacid ethyl ester; #158:4-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperazine-1-carboxylicacid tert-butyl ester; #159:1-(4-Chloro-phenyl)-3-[4-[2-((S)-3-methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#160:2-(4-Fluoro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#161:2-(4-Methoxy-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#162:1-(2,4-Difluoro-phenyl)-3-[4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#163:1-(2,4-Difluoro-phenyl)-3-[4-[2-(3-methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#164:1-(4-Chloro-phenyl)-3-[4-[2-((R)-3-methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#165:2-(2,4-Difluoro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#166:N-[4-[2-((2S,6R)-2,6-Dimethyl-morpholin-4-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#167: 1-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-chloro-phenyl)-urea;#168: Pentanoic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#169: 3-Hydroxy-pyridine-2-carboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#170:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-6-trifluoromethyl-nicotinamide;#171:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-6-methyl-nicotinamide;#172:5-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester; #173:2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-morpholine-4-carboxylicacid benzyl ester; #174:1-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(morpholin-2-ylmethoxy)-phenyl]-3-phenyl-urea;#175:(1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-3-yl)-aceticacid; #176:4-(4-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperazin-1-yl)-4-oxo-butyricacid methyl ester; #177:1-(4-Chloro-phenyl)-3-[4-[2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#178:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-6-hydroxy-nicotinamide;#179: Pentanoic acid{3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-amide;#180: Pentanoic acid{3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-amide;#181:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-6-methyl-nicotinamide;#182:1-(2,4-Difluoro-phenyl)-3-[4-[2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#183:1-[4-[2-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-fluoro-phenyl)-urea;#184:1-(4-Chloro-phenyl)-3-[4-[2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#185:1-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-pentanoylamino-phenoxy]-ethyl}-piperidine-4-carboxylicacid; #186:4-Chloro-N-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#187:4-(5-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-4-oxo-butyricacid methyl ester; #188:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperazin-1-yl-ethoxy)-phenyl]-urea;#189:1-[4-[2-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(3-fluoro-phenyl)-urea;#190:2-(4-Chloro-phenyl)-N-[4-[2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#191:4-(4-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperazin-1-yl)-4-oxo-butyricacid; #192:1-(2,4-Difluoro-phenyl)-3-[4-(1-methyl-piperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#193:[4-[2-((2S,6R)-2,6-Dimethyl-morpholin-4-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-carbamicacid isopropyl ester; #194:[(1-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-pentanoylamino-phenoxy]-ethyl}-piperidine-4-carbonyl)-amino]-aceticacid methyl ester; #195:[(1-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-pentanoylamino-phenoxy]-ethyl}-piperidine-4-carbonyl)-amino]-aceticacid; #196:(1H-Benzoimidazol-2-yl)-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-amine;#197:1-{2-[4-(Benzooxazol-2-ylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-4-carboxylicacid; #198:Benzothiazol-2-yl-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-amine;#199:Benzooxazol-2-yl-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-amine;#200:[(1-{2-[4-(Benzooxazol-2-ylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amino]-aceticacid methyl ester; #201:1-{2-[4-(Benzooxazol-2-ylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-4-carboxylicacid ethyl ester; #202:[(1-{2-[4-(Benzooxazol-2-ylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amino]-aceticacid; #203: Pentanoic acid[4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide;#204:3-(4-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-pentanoylamino-phenoxy]-ethyl}-piperazin-1-yl)-propionicacid ethyl ester; #205:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(pyrrolidin-2-ylmethoxy)-phenyl]-urea;#206:(4-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-pentanoylamino-phenoxy]-ethyl}-piperazin-1-yl)-aceticacid; #207:3-(4-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-pentanoylamino-phenoxy]-ethyl}-piperazin-1-yl)-propionicacid; #208:N-[4-[2-(4-Hydroxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-6-trifluoromethyl-nicotinamide;#209:(4-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperazin-1-yl)-aceticacid methyl ester; #210:4-(5-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-4-oxo-butyricacid; #211:3-(1-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-yl)-propionicacid; #212:(4-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperazin-1-yl)-aceticacid; #213: Pentanoic acid[4-[2-(3-methanesulfonyl-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide;#214:[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-carbamicacid isopropyl ester; #215:[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-carbamicacid isopropyl ester; #216:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-urea;#217:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-urea;#218:1-(4-Chloro-phenyl)-3-[4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#219:1-(2,4-Difluoro-phenyl)-3-[4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#220:1-(2,4-Difluoro-phenyl)-3-[4-[2-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#221:3-Methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-butyramide;#222:N-[4-[2-(3-Methoxy-azetidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#223: 4-Methyl-pentanoic acid{3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-amide;#224:1-(4-Chloro-phenyl)-3-[4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#225:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4,4-difluoro-piperidin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#226:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-phenyl-piperidin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#227:1-(2,4-Difluoro-phenyl)-3-[4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#228:2-(4-Chloro-phenyl)-N-[4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#229:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-fluoro-phenyl)-urea;#230:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(2-fluoro-phenyl)-urea;#231:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-chloro-phenyl)-urea;#232:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-phenyl-urea;#233:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3,5-difluoro-phenyl)-urea;#234:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(2,4-dichloro-phenyl)-urea;#235:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(4-chloro-2-trifluoromethyl-phenyl)-urea;#236:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-p-tolyl-urea;#237:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(4-methoxy-phenyl)-urea;#238:(1-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-pentanoylamino-phenoxy]-ethyl}-piperidin-4-yl)-aceticacid methyl ester; #239:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methanesulfonyl-piperazin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#240:(1-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-pentanoylamino-phenoxy]-ethyl}-piperidin-4-yl)-aceticacid; #241:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetamide;#242:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetamide;#243:[4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-carbamicacid isopropyl ester; #244:[4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-carbamicacid butyl ester; #245:1-(3-Fluoro-phenyl)-3-[4-(1-methyl-piperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#246:1-(2-Fluoro-phenyl)-3-[4-(1-methyl-piperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#247:1-(4-Methoxy-phenyl)-3-[4-(1-methyl-piperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#248:1-(3-Chloro-phenyl)-3-[4-(1-methyl-piperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#249:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-acetamide;#250:1-(4-Chloro-phenyl)-3-[4-[2-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#251:1-[4-[2-(1,1-Dioxo-1λ⁶-thiomorpholin-4-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-fluoro-phenyl)-urea;#252:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea;#253:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea;#254:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea;#255:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-ethoxy]-phenyl}-3-(2,4-difluoro-phenyl)-urea;#256:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea;#257:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea;#258:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3,4-difluoro-phenyl)-urea;#259:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea;#260:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-methoxy-phenyl)-urea;#261:1-(3-Acetyl-phenyl)-3-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-urea;#262:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(2,5-difluoro-phenyl)-urea;#263:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(2,6-difluoro-phenyl)-urea;#264:1-(3,5-Bis-trifluoromethyl-phenyl)-3-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-urea;#265:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-naphthalen-1-yl-urea;#266:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-acetamide;#267:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea;#268:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(2,4-difluoro-phenyl)-urea;#269:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-2-(4-chloro-phenyl)-acetamide;#270:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(4-fluoro-phenyl)-urea;#271: Cyclopropanecarboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#272: Thiophene-2-carboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#273:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-fluoro-benzamide;#274:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-(4-chloro-phenyl)-acetamide;#275:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-methyl-butyramide;#276: N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methyl-butyramide;#277:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-3-methyl-butyramide;#278:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-phenyl}-acetamide;#279:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea;#280:4-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#281:2,4-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#282:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#283:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-trifluoromethoxy-benzamide;#284:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(2,4-difluoro-phenyl)-urea;#285:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(4-fluoro-phenyl)-urea;#286:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(2-fluoro-phenyl)-urea;#287: Furan-2-carboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#288:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-fluoro-benzamide;#289:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-fluoro-benzamide;#290:1-[4-(1-Methyl-piperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-p-tolyl-urea;#291:1-(3-Cyano-phenyl)-3-[4-(1-methyl-piperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#292:1-(2-Fluoro-5-methyl-phenyl)-3-[4-(1-methyl-piperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#293:N-[4-[2-((2R,6S)-2,6-Dimethyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#294: Cyclopropanecarboxylic acid[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-amide;#295: Thiophene-2-carboxylic acid[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-amide;#296: Furan-2-carboxylic acid[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-amide;#297:4-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#298:1-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea;#299:1-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(2,4-difluoro-phenyl)-urea;#300:[1-(2-{2-(2-Methyl-2H-pyrazol-3-yl)-4-[(6-trifluoromethyl-pyridine-3-carbonyl)-amino]-phenoxy}-ethyl)-piperidin-4-yl]-aceticacid methyl ester; #301:[1-(2-{2-(2-Methyl-2H-pyrazol-3-yl)-4-[(6-trifluoromethyl-pyridine-3-carbonyl)-amino]-phenoxy}-ethyl)-piperidin-4-yl]-aceticacid; #302:3-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#303:2-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#304:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea;#305:[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-(4-chloro-phenyl)-amine;#306:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-cyclopropyl-acetamide;#307:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-cyclopentyl-acetamide;#308: Cyclopropanecarboxylic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#309: Cyclobutanecarboxylic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#310: Cyclopentanecarboxylic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#311:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethylamino)-phenyl]-urea;#312:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethylamino)-phenyl]-urea;#313:2-(4-Chloro-phenyl)-2,2-difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#314:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(4-fluoro-phenyl)-urea;#315:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(4-methoxy-phenyl)-urea;#316:1-(4-Bromo-phenyl)-3-[4-(1-methyl-piperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#317:1-[4-(1-Methyl-piperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2-trifluoromethoxy-phenyl)-urea;#318:1-[4-(1-Methyl-piperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea;#319:1-(4-Chloro-phenyl)-3-[4-[2-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#320:1-(2,4-Difluoro-phenyl)-3-[4-[2-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#321:1-[4-[2-((2S,6R)-2,6-Dimethyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-fluoro-phenyl)-urea;#322:4-(2-{2-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[3-(4-chloro-phenyl)-ureido]-phenoxy}-ethyl)-piperidine-1-carboxylicacid tert-butyl ester; #323:4-{2-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[3-(4-chloro-phenyl)-ureido]-phenoxymethyl}-piperidine-1-carboxylicacid tert-butyl ester; #324:1-[4-[2-((2R,6S)-2,6-Dimethyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-methoxy-phenyl)-urea;#325:2-(4-Chloro-phenyl)-N-[4-[2-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#326:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-3-methyl-butyramide;#327: Thiophene-2-carboxylic acid[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-amide;#328:2-(4-Chloro-phenyl)-2,2-difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-acetamide;#329:1-(4-Chloro-phenyl)-3-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-urea;#330:3-Methyl-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-butyramide;#331:(R)-2-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester; #332:4-{2-(2-Methyl-2H-pyrazol-3-yl)-4-[(thiophene-2-carbonyl)-amino]-phenoxymethyl}-piperidine-1-carboxylicacid tert-butyl ester; #333: 5-Chloro-thiophene-2-carboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#334:1-[4-(1-Acetyl-piperidin-4-ylmethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-chloro-phenyl)-urea;#335:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-3-(4-chloro-phenyl)-urea;#336: Thiophene-2-carboxylic acid[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide;#337: Thiophene-2-carboxylic acid[4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide;#338: Thiophene-2-carboxylic acid[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#339:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-((R)-2-piperidin-2-yl-ethoxy)-phenyl]-urea;#340:1-(4-Chloro-phenyl)-3-[4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#341:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-phenyl}-2-(4-chloro-phenyl)-acetamide;#342:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(4-chloro-phenyl)-2,2-difluoro-acetamide;#343:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#344: Thiophene-2-carboxylic acid[3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)-phenyl]-amide;#345: Thiophene-2-carboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide;#346:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,5-difluoro-phenyl)-urea;#347: Thiophene-2-carboxylic acid[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-amide;#348: Thiophene-2-carboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-amide;#349:(R)-4-Benzyloxy-2-{2-[4-[3-(4-fluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-pyrrolidine-1-carboxylicacid ethyl ester; #350:1-[4-(2-Azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-chloro-phenyl)-urea;#351:1-[4-(2-Azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,4-difluoro-phenyl)-urea;#352:[4-(2-Azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-carbamicacid isopropyl ester; #353:1-(4-Chloro-phenyl)-3-[4-[2-((R)-1-methyl-piperidin-2-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#354:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-2-(4-chloro-phenyl)-2,2-difluoro-acetamide;#355:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-propoxy)-phenyl]-urea;#356:1-(4-Chloro-2-fluoro-phenyl)-3-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea;#357: Thiophene-2-carboxylic acid[4-(1-methyl-piperidin-4-ylmethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide;#358:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-propoxy)-phenyl]-urea;#359:1-(4-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-propoxy)-phenyl]-urea;#360:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-fluoro-benzamide;#361:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(4-chloro-phenyl)-acetamide;#362:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-cyclopentyl-acetamide;#363:1-(4-Chloro-phenyl)-3-[4-(1-methyl-piperidin-4-ylmethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#364:(R)-3-[4-[2-(4-Chloro-phenyl)-2-hydroxy-acetylamino]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-1-carboxylicacid tert-butyl ester; #365:(R)-3-[4-[3-(4-Fluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-1-carboxylicacid tert-butyl ester; #366:(R)-3-[2-(2-Methyl-2H-pyrazol-3-yl)-4-(4-trifluoromethyl-benzoylamino)-phenoxy]-pyrrolidine-1-carboxylicacid tert-butyl ester; #367:2-(4-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-propoxy)-phenyl]-acetamide;#368:2-(4-Chloro-phenyl)-2,2-difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-propoxy)-phenyl]-acetamide;#369:2-(4-Chloro-phenyl)-N-[4-(1-methyl-piperidin-4-ylmethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#370:1-(4-Chloro-phenyl)-3-[4-(1-methyl-2-morpholin-4-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#371:2-(4-Chloro-phenyl)-2-hydroxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-((R)-pyrrolidin-3-yloxy)-phenyl]-acetamide;#372:1-(4-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-((R)-pyrrolidin-3-yloxy)-phenyl]-urea;#373:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-((R)-pyrrolidin-3-yloxy)-phenyl]-4-trifluoromethyl-benzamide;#374:4-[4-Acetylamino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-piperidine-1-carboxylicacid tert-butyl ester; #375:1-(2,4-Difluoro-phenyl)-3-[4-(1-methyl-2-morpholin-4-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#376:2-(4-Chloro-phenyl)-N-[4-(1-methyl-2-morpholin-4-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#377:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(4-chloro-phenyl)-acetamide;#378:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)-phenyl]-3-(4-chloro-phenyl)-urea;#379:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,3-difluoro-phenyl)-urea;#380: Thiophene-2-carboxylic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)-phenyl]-amide;#381:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)-phenyl]-2-(4-chloro-phenyl)-acetamide;#382: Thiophene-2-carboxylic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-amide;#383:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-(4-chloro-phenyl)-acetamide;#384:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4,5-trifluoro-phenyl)-urea;#385:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,3,4-trifluoro-phenyl)-urea;#386:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-((R)-pyrrolidin-3-yloxy)-phenyl]-4-trifluoromethyl-benzamide;#387:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-((R)-pyrrolidin-3-yloxy)-phenyl]-4-chloro-benzamide;#388:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-((R)-pyrrolidin-3-yloxy)-phenyl]-4-fluoro-benzamide;#389:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-((R)-pyrrolidin-3-yloxy)-phenyl]-2,4-difluoro-benzamide;#390:4-Chloro-N-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#391:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-((R)-pyrrolidin-3-yloxy)-phenyl]-3-(4-chloro-phenyl)-urea;#392:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-((R)-pyrrolidin-3-yloxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea;#393:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)-phenyl]-urea;#394:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)-phenyl]-3-(4-fluoro-phenyl)-urea;#395:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)-phenyl]-4-chloro-benzamide;#396:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)-phenyl]-4-fluoro-benzamide;#397:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)-phenyl]-2,4-difluoro-benzamide;#398:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)-phenyl]-2-(4-fluoro-phenyl)-2-hydroxy-acetamide;#399:4-Fluoro-N-[3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#400:2-(4-Chloro-phenyl)-N-[3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#401:1-(4-Chloro-phenyl)-3-[4-(1,1-dimethyl-2-pyrrolidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#402:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)-phenyl]-4-trifluoromethyl-benzamide;#403:1-[4-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-fluoro-phenyl)-urea;#404:2-(4-Chloro-phenyl)-N-[4-(1,1-dimethyl-2-pyrrolidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#405:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-chloro-phenyl)-urea;#406:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-fluoro-phenyl)-urea;#407:1-(2,4-Difluoro-phenyl)-3-[4-(1,1-dimethyl-2-pyrrolidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#408:3,4-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#409:2,4-Dichloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#410:3,4-Dichloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#411:3-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#412:5-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-2-trifluoromethyl-benzamide;#413:3,5-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#414:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#415:2-(4-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-isobutyramide;#416: 1-(4-Chloro-phenyl)-cyclopropanecarboxylic acid[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-amide;#417:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(4-chloro-phenyl)-isobutyramide;#418: 1-(4-Chloro-phenyl)-cyclopropanecarboxylic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide;#419:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(4-chloro-phenyl)-2-hydroxy-acetamide;#420:1-[4-((R)-1-Benzyl-pyrrolidin-3-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-chloro-phenyl)-urea;#421:1-(4-Chloro-phenyl)-3-[4-[2-((S)-3-fluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#422:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-((R)-piperidin-3-yloxy)-phenyl]-urea;#423:2-(4-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-((R)-piperidin-3-yloxy)-phenyl]-acetamide;#424:2,4-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#425:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#426:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-2-trifluoromethyl-benzamide;#427:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-chloro-phenyl)-acetamide;#428:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,4-difluoro-phenyl)-urea;#429:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,5-difluoro-phenyl)-urea;#430:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-chloro-benzamide;#431:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-benzamide;#432: Benzo[b]thiophene-2-carboxylic acid[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-amide;#433:2-(4-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-((S)-piperidin-3-yloxy)-phenyl]-acetamide;#434:2-(4-Chloro-phenyl)-2-hydroxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-((S)-piperidin-3-yloxy)-phenyl]-acetamide;#435:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#436:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-2-thiophen-2-yl-acetamide;#437:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(4-fluoro-phenyl)-propionamide;#438:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-yloxy)-phenyl]-urea;#439:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-yloxy)-phenyl]-urea;#440:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#441:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3,4-difluoro-benzamide;#442:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-pyrrolidin-1-yl-propoxy)-phenyl]-urea;#443:2-(4-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-pyrrolidin-1-yl-propoxy)-phenyl]-acetamide;#444:3,4-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-yloxy)-phenyl]-benzamide;#445:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(piperidin-4-yloxy)-phenyl]-4-trifluoromethyl-benzamide;#446:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-pyrrolidin-1-yl-propoxy)-phenyl]-4-trifluoromethyl-benzamide;#447:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-2-(4-fluoro-phenyl)-2-hydroxy-acetamide;#448:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-2-(2-chloro-phenyl)-2-hydroxy-acetamide;#449:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-4-fluoro-benzamide;#450:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-fluoro-benzamide;#451:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#452:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#453:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3,4-difluoro-benzamide;#454:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#455:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-fluoro-benzamide;#456:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3,4-difluoro-benzamide;#457:N-[4-[2-(2-Methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#458:3-Fluoro-N-[4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;#459:3,4-Difluoro-N-[4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;#460:1-(4-Chloro-phenyl)-3-[4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#461:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-propionamide;#462:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4-dichloro-phenyl)-propionamide;#463:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-thiazol-2-yl-propionamide;#464:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-pyridin-3-yl-propionamide;#465:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-hydroxy-phenyl)-propionamide;#466:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-methoxy-phenyl)-propionamide;#467:2-(4-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-yloxy)-phenyl]-acetamide;#468:2,4-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#469:3,4-Dichloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#470:N-[4-[2-((S)-3-Fluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#471:N-[4-[2-((S)-3-Fluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#472:N-[4-[2-((S)-3-Fluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methyl-benzamide;#473:3-Fluoro-N-[4-[2-((S)-3-fluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;#474:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-((S)-3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenyl}-4-fluoro-benzamide;#475:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-((S)-3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenyl}-3-fluoro-benzamide;#476:4-Chloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-pyrrolidin-1-yl-propoxy)-phenyl]-benzamide;#477:2-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#478:1-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea;#479:4-Chloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#480:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#481:N-[4-[2-(4-Fluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#482:N-[4-[2-(4-Fluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#483:3,4-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#484:3-Chloro-4-fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#485:4-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#486:4-Fluoro-3-methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#487:3-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#488:3-Fluoro-4-methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#489:4-Chloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#490:3,4-Dichloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#491:4-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#492:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#493:3-Chloro-4-fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#494:4-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#495:3-Fluoro-4-methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#496:4-Fluoro-3-methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#497:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2,4-difluoro-benzamide;#498:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-chloro-benzamide;#499:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-methyl-benzamide;#500:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#501:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-chloro-benzamide;#502:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#503:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-2,4-difluoro-benzamide;#504:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-4-chloro-benzamide;#505:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-4-methyl-benzamide;#506:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#507:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-chloro-benzamide;#508:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#509:4-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#510:4-Methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#511:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-trifluoromethoxy-benzamide;#512:3-Chloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#513:3-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#514:1-(4-Chloro-phenyl)-3-[4-(2-methyl-2-morpholin-4-yl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#515:N-[4-(2-Methyl-2-morpholin-4-yl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#516:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-fluoro-benzamide;#517:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-fluoro-benzamide;#518:N-[4-(2-Methyl-2-morpholin-4-yl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#519:4-Chloro-3-fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#520:4-Chloro-N-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-fluoro-benzamide;#521:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(4-fluoro-phenyl)-propionamide;#522:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-fluoro-phenyl)-propionamide;#523:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-propionamide;#524:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2,4-difluoro-benzamide;#525:3,4-Dichloro-N-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#526:3-Chloro-N-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-fluoro-benzamide;#527:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#528:3-Chloro-N-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#529:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-methyl-benzamide;#530:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-trifluoromethoxy-benzamide;#531:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-methoxy-benzamide;#532:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-methyl-benzamide;#533:N-{3-(2-Methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#534:2,4-Difluoro-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-benzamide;#535:3-Chloro-4-fluoro-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-benzamide;#536:N-[4-[2-(3,3-Difluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#537:4-Fluoro-N-[4-[2-(4-fluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methyl-benzamide;#538:3-Chloro-4-fluoro-N-[4-[2-(4-fluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;#539:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-((S)-1-methyl-pyrrolidin-2-ylmethoxy)-phenyl]-3-trifluoromethyl-benzamide;#540:3-Chloro-4-fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-((S)-1-methyl-pyrrolidin-2-ylmethoxy)-phenyl]-benzamide;#541:4-Chloro-3-fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide;#542:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-pyridin-3-yl-propionamide;#543:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-thiophen-2-yl-propionamide;#544:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-thiazol-2-yl-propionamide;#545:3-Chloro-N-[4-[2-(3,3-difluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-benzamide;#546:N-[4-[2-(3,3-Difluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-3-methyl-benzamide;#547:4-Fluoro-3-methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-((S)-1-methyl-pyrrolidin-2-ylmethoxy)-phenyl]-benzamide;#548:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2,4-difluoro-benzamide;#549: 5-Methyl-isoxazole-3-carboxylic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#550:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(2,4-dichloro-phenyl)-propionamide;#551:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(2-chloro-phenyl)-propionamide;#552:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(2,6-dichloro-phenyl)-propionamide;#553:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(4-methoxy-phenyl)-propionamide;#554:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(4-hydroxy-phenyl)-propionamide;#555:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-((R)-1-methyl-pyrrolidin-3-yloxy)-phenyl]-3-trifluoromethyl-benzamide;#556:3-Chloro-4-fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-((R)-1-methyl-pyrrolidin-3-yloxy)-phenyl]-benzamide;#557: 5-Methyl-isoxazole-3-carboxylic acid[3-(2-methyl-2H-pyrazol-3-yl)-4-((R)-1-methyl-pyrrolidin-3-yloxy)-phenyl]-amide;#558:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-fluoro-4-trifluoromethyl-benzamide;#559:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-fluoro-4-methyl-benzamide;#560:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-fluoro-3-trifluoromethyl-benzamide;#561:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-fluoro-3-methyl-benzamide;#562:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-isonicotinamide;#563:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-nicotinamide;#564:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#565:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-cyano-benzamide;#566:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#567:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-4-trifluoromethoxy-benzamide;#568:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#569:3,4-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-benzamide;#570:4-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-benzamide;#571:4-Fluoro-3-methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-benzamide;#572:N-{3-(2-Methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#573:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-fluoro-4-trifluoromethyl-benzamide;#574:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(4-trifluoromethyl-phenyl)-propionamide;#575:N-[4-[2-((S)-3-Hydroxy-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#576:3-Chloro-4-fluoro-N-[4-[2-((S)-3-hydroxy-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;#577:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-((S)-3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenyl}-2,4-difluoro-benzamide;#578:3-Chloro-4-fluoro-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenyl}-benzamide;#579:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenyl}-3,4-difluoro-benzamide;#580:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenyl}-2,4-difluoro-benzamide;#581:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#582:4-Fluoro-N-[4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#583:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-((R)-1-methyl-pyrrolidin-3-yloxy)-phenyl]-2,4-difluoro-benzamide;#584:N-[4-[2-((R)-3-Hydroxy-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#585:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-((R)-1-methyl-pyrrolidin-3-yloxy)-phenyl]-3,4-difluoro-benzamide;#586:N-[4-[2-((S)-3-Hydroxy-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#587:N-[4-((S)-4-Benzyl-morpholin-3-ylmethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#588:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#589:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#590:1-[4-[2-(2-Methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea;#591:1-[4-[2-(2-Methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea;#592:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-((S)-1-morpholin-3-ylmethoxy)-phenyl]-3-trifluoromethyl-benzamide;#593:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-((R)-1-morpholin-3-ylmethoxy)-phenyl]-3-trifluoromethyl-benzamide;#594:N-[4-((R)-4-Benzyl-morpholin-3-ylmethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#595:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-benzamide;#596:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide;#597:3-Fluoro-N-[4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#598:3,4-Difluoro-N-[4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;#599:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-chloro-phenyl)-acetamide;#600:N-[4-[2-(4-Methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#601:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-chloro-benzamide;#602:N-[4-[2-(4-Methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#603:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-benzamide;#604:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#605:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#606:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-fluoro-4-trifluoromethyl-benzamide;#607:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-4-fluoro-3-methyl-benzamide;#608:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-4-fluoro-3-trifluoromethyl-benzamide;#609:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#610:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#611:1-[4-[2-(4-Methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea;#612:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-3-fluoro-4-trifluoromethyl-benzamide;#613:1-[4-[2-(4-Methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea;#614:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-4-fluoro-3-trifluoromethyl-benzamide;#615:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-((S)-3-hydroxy-pyrrolidin-1-yl)-ethoxy]-phenyl}-2,4-difluoro-benzamide;#616:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-((S)-3-hydroxy-pyrrolidin-1-yl)-ethoxy]-phenyl}-4-chloro-benzamide;#617:1-[4-((R)-4-Benzyl-morpholin-3-ylmethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-chloro-phenyl)-urea;#618:4-Chloro-N-[4-[2-((R)-3-hydroxy-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;#619:2-(4-Chloro-phenyl)-N-[4-[2-((R)-3-hydroxy-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#620:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-4-trifluoromethyl-benzamide;#621:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-3-trifluoromethyl-benzamide;#622:N-{3-(2-Methyl-2H-pyrazol-3-yl)-4-[2-(3-oxo-piperazin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#623:2-(4-Chloro-phenyl)-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(3-oxo-piperazin-1-yl)-ethoxy]-phenyl}-acetamide;#624:4-Fluoro-3-methyl-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(3-oxo-piperazin-1-yl)-ethoxy]-phenyl}-benzamide;#625:N-[4-[2-(4-Hydroxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#626:N-[4-[2-(4-Hydroxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#627:N-[4-{2-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-ethoxy}-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#628:2-(4-Chloro-phenyl)-N-[4-{2-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-ethoxy}-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#629:4-Fluoro-3-methyl-N-[4-{2-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-ethoxy}-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;#630:2-(4-Chloro-phenyl)-N-[4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#631:1-(4-Chloro-benzyl)-3-[4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#632:1-(4-Fluoro-benzyl)-3-[4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#633:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenyl}-4-trifluoromethyl-benzamide;#634:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#635:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenyl}-3,4-difluoro-benzamide;#636:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenyl}-4-fluoro-benzamide;#637:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenyl}-3-fluoro-benzamide;#638:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4-difluoro-benzamide;#639:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3,4-dichloro-benzamide;#640:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-phenyl}-4-trifluoromethyl-benzamide;#641:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-phenyl}-3,4-difluoro-benzamide;#642:1-(4-Chloro-benzyl)-3-{3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-phenyl}-urea;#643:1-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-phenyl}-3-(4-fluoro-benzyl)-urea;#644:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-phenyl}-4-trifluoromethyl-benzamide;#645:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-phenyl}-3,4-difluoro-benzamide;#646:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-phenyl}-3-(4-fluoro-benzyl)-urea;#647:4-Chloro-N-{3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-oxo-piperazin-1-yl)-ethoxy]-phenyl}-benzamide;#648:1-(4-Chloro-benzyl)-3-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-urea;#649:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(4-fluoro-benzyl)-urea;#650:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-fluoro-benzyl)-urea;#651:4-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-(4-trifluoromethyl-benzoylamino)-phenoxy]-ethyl}-piperazine-1-carboxylicacid ethyl ester; #652:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-oxo-piperazin-1-yl)-ethoxy]-phenyl}-4-fluoro-benzamide;#653:4-{2-[4-(3-Fluoro-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperazine-1-carboxylicacid ethyl ester; #654:4-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperazine-1-carboxylicacid ethyl ester; #655:(1-{2-[4-(3-Fluoro-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-yl)-carbamicacid tert-butyl ester; #656:(1-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-ethyl}-piperidin-4-yl)-carbamicacid tert-butyl ester; #657:(1-{2-[4-[2-(4-Chloro-phenyl)-acetylamino]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-yl)-carbamicacid tert-butyl ester; #658:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-benzyl-urea;#659:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#660:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide;#661:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-chloro-phenyl)-acetamide;#662:(1-{2-[4-(3-Fluoro-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-yl)-carbamicacid ethyl ester; #663:(1-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-ethyl}-piperidin-4-yl)-carbamicacid ethyl ester; #664:1-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea;#665:1-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea;#666:1-(4-Chloro-benzyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-urea;#667:2-(4-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-acetamide;#668:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-4-trifluoromethyl-benzamide;#669:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-3-trifluoromethyl-benzamide;#670:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-oxo-piperazin-1-yl)-ethoxy]-phenyl}-3-chloro-benzamide;#671:1-(3-Fluoro-benzyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-urea;#672:4-Chloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-benzamide;#673:3,4-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-benzamide;#674:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-oxo-piperazin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#675:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-oxo-piperazin-1-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea;#676:1-(4-Fluoro-benzyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-urea;#677:N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-oxo-piperazin-1-yl)-ethoxy]-phenyl}-3-fluoro-benzamide;#678:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methyl-3-oxo-piperazin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#679:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-4-trifluoromethyl-benzamide;#680:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-3-trifluoromethyl-benzamide;#681:4-Chloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-benzamide;#682:3,4-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-benzamide;#683:2-(4-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-acetamide;#684:1-(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-urea;#685:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-urea;#686:1-(4-Chloro-benzyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-urea;#687:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-oxo-piperazin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#688:N-[4-(3-Imidazol-1-yl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#689:N-[4-(3-Imidazol-1-yl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#690:2-(4-Chloro-phenyl)-N-[4-(3-imidazol-1-yl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide;#691:1-(4-Chloro-phenyl)-3-[4-(3-imidazol-1-yl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea;#692:1-[4-((S)-4-Benzyl-morpholin-3-ylmethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-fluoro-phenyl)-urea;#693:1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-((S)-1-morpholin-3-ylmethoxy)-phenyl]-3-(4-fluoro-phenyl)-urea;#694:N-[4-((S)-4-Benzyl-morpholin-3-ylmethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#695:3-Chloro-N-{3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methyl-3-oxo-piperazin-1-yl)-ethoxy]-phenyl}-benzamide;#696:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-((S)-1-morpholin-3-ylmethoxy)-phenyl]-3-trifluoromethyl-benzamide;#697:4-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-ethyl}-4-methyl-morpholin-4-ium;#698:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2-fluoro-benzyl)-urea;#699:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(3-fluoro-benzyl)-urea;#700:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-fluoro-benzyl)-urea;#701:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,4-dichloro-benzyl)-urea;#702:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(1-phenyl-ethyl)-urea;#703:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#704:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide;#705:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-benzamide;#706:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-4-fluoro-benzamide;#707:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;#708:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-benzamide;#709:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-benzyl)-urea;#710:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(3-trifluoromethyl-benzyl)-urea;#711:1-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-fluoro-phenyl)-urea;#712:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-chloro-benzyl)-urea;#713:(S)-1-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid amide; #714:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-formyl-piperazin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#715:1-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-ethyl}-piperidine-4-carboxylicacid amide; #716:4-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-ethyl}-piperazine-1-carboxylicacid amide; #717:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-acetamide;#718:(1-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-ethyl}-piperidin-4-yl)-carbamicacid tert-butyl ester; #719:N-[4-[2-(4-Amino-piperidin-1-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#720:N-[4-[2-(4-Acetylamino-piperidin-1-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#721:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2-chloro-benzyl)-urea;#722:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2-fluoro-benzyl)-urea;#723:4-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-ethyl}-piperazine-1-carboxylicacid dimethylamide; #724:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-isopropyl-piperazin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#725:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3,3-difluoro-pyrrolidin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#726:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-3-trifluoromethyl-benzamide;#727:3-Chloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#728:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-3-trifluoromethyl-benzamide;#729:3-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#730:3,4-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#731:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4-difluoro-benzamide;#732:3-Fluoro-4-methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#733:3-Methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#734:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,4-difluoro-benzyl)-urea;#735:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3,3-difluoro-azetidin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#736:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(3-fluoro-benzyl)-urea;#737:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2-fluoro-benzyl)-urea;#738:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-fluoro-benzyl)-urea;#739:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-4-fluoro-benzamide;#740:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-3-fluoro-benzamide;#741:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-2-fluoro-benzamide;#742:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-3-methoxy-benzamide;#743:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-4-methyl-benzamide;#744:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-3-fluoro-4-methyl-benzamide;#745:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-4-fluoro-3-methyl-benzamide;#746:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-benzyl-urea;#747:1-{2-[4-(3-Fluoro-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-4-carboxylicacid amide; #748:4-{2-[4-(3-Fluoro-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperazine-1-carboxylicacid amide; #749:1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-benzoyl-urea;#750:N-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;#751:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#752:3-Fluoro-N-[4-[2-(4-formyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;#753:3-Fluoro-N-[4-[2-(4-methanesulfonyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;#754:3-Fluoro-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(4-trifluoromethyl-piperidin-1-yl)-ethoxy]-phenyl}-benzamide;#755:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide;#756:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-oxo-2-piperazin-1-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide;#757:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methanesulfonylamino-piperidin-1-yl)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide;#758:N-[4-[2-(4-Acetyl-[1,4]diazepan-1-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4-difluoro-benzamide;#759:2,5-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#760:3,5-Dimethoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#761:3,5-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;#762:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-phenyl-acetamide;#763:2-(2-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#764:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-(2-trifluoromethyl-phenyl)-acetamide;#765:2-(2-Methoxy-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#766:2-(3-Fluoro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#767:2-(3-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#768:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-acetamide;#769:2-(3-Methoxy-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#770:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-m-tolyl-acetamide;#771:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-p-tolyl-acetamide;#772:2-Benzo[1,3]dioxol-5-yl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#773:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-o-tolyl-acetamide;#774:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]diazepan-1-yl-ethoxy)-phenyl]-2,4-difluoro-benzamide;#775:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methyl-[1,4]diazepan-1-yl)-ethoxy]-phenyl}-2,4-difluoro-benzamide;#776:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4-difluoro-benzamide;#777:1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-fluoro-benzyl)-urea;#778:N-[4-[2-(4,4-Difluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide;#779: Cyclobutanecarboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#780: Cyclopentanecarboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#781: Cyclohexanecarboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide;#782:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-formyl-[1,4]diazepan-1-yl)-ethoxy]-phenyl}-2,4-difluoro-benzamide;#783:1-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(3-fluoro-benzyl)-urea;#784:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-2,4-difluoro-benzamide;#785:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-3-methyl-benzamide;#786:4-{2-[4-(2,4-Difluoro-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperazine-1-carboxylicacid amide; #787:N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-benzamide;#788:1-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-fluoro-benzoylamino)-phenoxy]-ethyl}-piperidine-4-carboxylicacid amide; #789:3-Methoxy-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(4-trifluoromethyl-piperidin-1-yl)-ethoxy]-phenyl}-benzamide;#790:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-piperazin-1-yl-ethoxy)-phenyl]-2,4-difluoro-benzamide;#791:4-{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperazine-1-carboxylicacid amide; #792:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-pyridin-3-yl-acetamide;#793:2-(2-Fluoro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide;#794:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide;#795:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-thiophen-2-yl-acetamide;#796:3-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperazin-1-yl-ethoxy)-phenyl]-benzamide;#797:N-[4-[2-(4-Cyclopropanecarbonyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide;#798:3-Fluoro-N-[4-[2-(4-isobutyryl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;#799:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-pyridin-2-yl-acetamide;#800:(R)-1-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid amide; #801:(R)-1-{2-[4-(3-Chloro-4-fluoro-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid amide; #802:(S)-1-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-(4-trifluoromethyl-benzoylamino)-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid amide; #803:(S)-1-{2-[4-(3-Chloro-4-fluoro-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid amide; #804:(S)-1-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid amide; #805:N-[4-[2-(4-Amino-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide;#806:N-[4-[2-(4-Amino-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#807:N-[4-[2-(4-Amino-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-(4-chloro-phenyl)-acetamide;#808:[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-(4-trifluoromethyl-phenyl)-amine;#809:[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-(4-chloro-phenyl)-amine;#810:[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-(4-fluoro-phenyl)-amine;#811:[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-(3-fluoro-phenyl)-amine;#812:[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-(4-trifluoromethyl-phenyl)-amine;#813:[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-(4-fluoro-phenyl)-amine;#814:[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-(3-chloro-phenyl)-amine;#815:[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-(3-fluoro-phenyl)-amine;#816:[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-(3,4-difluoro-phenyl)-amine;#817:[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-(4-trifluoromethoxy-phenyl)-amine;#818:[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-3-yl-amine;#819:1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-piperidin-4-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea;#820: Thiophene-2-carboxylic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide;#821:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-fluoro-benzamide;#822:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(4-chloro-phenyl)-acetamide;#823:3,4-Dichloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-benzamide;#824:N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide;#825:N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-fluoro-benzamide;#826:4-Fluoro-N-[4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;#827:N-[4-[2-(8-Acetyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide;#828:N-[4-[2-(3-Acetyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide;#829:N-[4-[2-(8-Acetyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide;#830:N-[4-[2-(3-Acetyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide;#831:(S)-3-[4-[3-(2,4-Difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-1-carboxylicacid tert-butyl ester; #832:(R)-3-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-pyrrolidine-1-carboxylicacid tert-butyl ester; #833:(R)-2-[4-[3-(2,4-Difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester; #834:(R)-2-[4-[3-(4-Fluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester; #835:1-(4-Chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-((R)-pyrrolidin-3-yloxy)-phenyl]-urea;and #836:1-(4-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-((S)-1-pyrrolidin-2-ylmethoxy)-phenyl]-urea.

Additionally, individual compounds and chemical genera of the presentinvention, such as Formula (Ia) and related Formulae therefrom,encompass all pharmaceutically acceptable salts, solvates, andparticularly hydrates, thereof.

It is understood that the present invention embraces each diastereomer,each enantiomer and mixtures thereof of each compound and genericFormulae disclosed herein just as if they were each individuallydisclosed with the specific stereochemical designation for each chiralatom, for example carbon.

The compounds of the Formula (Ia) of the present invention can beprepared according to the general synthetic schemes in FIG. 1 through 12as well as relevant published literature procedures that are used by oneskilled in the art. Exemplary reagents and procedures for thesereactions appear hereinafter in the working Examples. Protection anddeprotection may be carried out by procedures generally known in the art(see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groupsin Organic Synthesis, 3^(rd) Edition, 1999 [Wiley]; incorporated hereinby reference in its entirity).

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers (such as, chiral HPLC,recrystallization of diastereomeric mixture, and the like) or selectivesynthesis (such as, enantiomeric selective synthesis, and the like) ofthe individual isomers is accomplished by application of various methodswhich are well known to practitioners in the art.

Indications and Methods of Treatment

In addition to the foregoing beneficial uses for the modulators of5-HT_(2A) receptor activity disclosed herein, the compounds disclosedherein are believed to be useful in the treatment of several additionaldiseases and disorders, and in the amelioration of symptoms thereof.Without limitation, these include the following:

1. Antiplatelet Therapies (Conditions Related to Platelet Aggregation):

Antiplatelet agents (antiplatelets) are prescribed for a variety ofconditions. For example, in coronary artery disease they are used tohelp prevent myocardial infarction or stroke in patients who are at riskof developing obstructive blood clots (e.g., coronary thrombosis).

In a myocardial infarction (heart attack), the heart muscle does notreceive enough oxygen-rich blood as a result of a blockage in thecoronary blood vessels. If taken while an attack is in progress orimmediately afterward (preferably within 30 minutes), antiplatelets canreduce the damage to the heart.

A transient ischemic attack (“TIA” or “mini-stroke”) is a briefinterruption of oxygen flow to the brain due to decreased blood flowthrough arteries, usually due to an obstructing blood clot. Antiplateletdrugs have been found to be effective in preventing TIAs.

Angina is a temporary and often recurring chest pain, pressure ordiscomfort caused by inadequate oxygen-rich blood flow (ischemia) tosome parts of the heart. In patients with angina, antiplatelet therapycan reduce the effects of angina and the risk of myocardial infarction.

Stroke is an event in which the brain does not receive enoughoxygen-rich blood, usually due to blockage of a cerebral blood vessel bya blood clot. In high-risk patients, taking antiplatelets regularly hasbeen found to prevent the formation of blood clots that cause first orsecond strokes.

Angioplasty is a catheter based technique used to open arteriesobstructed by a blood clot. Whether or not stenting is performedimmediately after this procedure to keep the artery open, antiplateletscan reduce the risk of forming additional blood clots following theprocedure(s).

Coronary bypass surgery is a surgical procedure in which an artery orvein is taken from elsewhere in the body and grafted to a blockedcoronary artery, rerouting blood around the blockage and through thenewly attached vessel. After the procedure, antiplatelets can reduce therisk of secondary blood clots.

Atrial fibrillation is the most common type of sustained irregular heartrhythm (arrythmia). Atrial fibrillation affects about two millionAmericans every year. In atrial fibrillation, the atria (the heart'supper chambers) rapidly fire electrical signals that cause them toquiver rather than contract normally. The result is an abnormally fastand highly irregular heartbeat. When given after an episode of atrialfibrillation, antiplatelets can reduce the risk of blood clots formingin the heart and traveling to the brain (embolism).

5-HT_(2A) receptors are expressed on smooth muscle of blood vessels and5-HT secreted by activated platelets causes vasoconstriction as well asactivation of additional platelets during clotting. There is evidencethat a 5-HT_(2A) inverse agonist will inhibit platelet aggregation andthus be a potential treatment as an antiplatelet therapy (see Satimura,K, et al., Clin Cardiol 2002 Jan. 25 (1):28-32; and Wilson, H. C. etal., Thromb Haemost 1991 Sep. 2; 66(3):355-60).

5-HT_(2A) inverse agonists can be used to treat, for example,claudication or peripheral artery disease as well as cardiovascularcomplications (see Br. Med. J. 298: 424-430, 1989), Arterial thrombosis(see, Pawlak, D. et al. Thrombosis Research 90: 259-270, 1998),atherosclerosis (see, Hayashi, T. et al. Atherosclerosis 168: 23-31,2003), vasoconstriction, caused by serotonin (see, Fujiwara, T. andChiba, S. Journal of Cardiovascular Pharmacology 26: 503-510, 1995),restenosis of arteries following angioplasty or stent placement (see,Fujita, M. et al. Am Heart J. 145:e16 2003). It can also be used aloneor in combination with thrombolytic therapy, for example, tPA (see,Yamashita, T. et al. Haemostasis 30:321-332, 2000), to providecardioprotection following MI or postischemic myocardial dysfunction(see, Muto, T. et al. Mol. Cell. Biochem. 272: 119-132, 2005) orprotection from ischemic injury during percutaneous coronaryintervention (see, Horibe, E. Circulation Research 68: 68-72, 2004), andthe like, including complications resulting therefrom.

5-HT_(2A) inverse antagonists can increase circulating adiponectin inpatients, suggesting that they would also be useful in protectingpatients against indications that are linked to adiponectin, forexample, myocardial ischemia reperfusion injury and artherosclerosis(see Nomura, Shosaku, et al. Blood Coagulation and Fibrinolysis 2005,16, 423-428).

The 5-HT_(2A) inverse agonists disclosed herein provide beneficialimprovement in microcirculation to patients in need of antiplatelettherapy by antagonizing the vasoconstrictive products of the aggregatingplatelets in, for example and not limited to the indications describedabove. Accordingly, in some embodiments, the present invention providesmethods for reducing platelet aggregation in a patient in need thereofcomprising administering to the patient a composition comprising a5-HT_(2A) inverse agonist disclosed herein. In further embodiments, thepresent invention provides methods for treating coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, atrialfibrillation, or a symptom of any of the foregoing in a patient in needof the treatment, comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein.

In further embodiments, the present invention provides methods forreducing risk of blood clot formation in an angioplasty or coronarybypass surgery patient, or a patient suffering from atrial fibrillation,comprising administering to the patient a composition comprising a5-HT_(2A) inverse agonist disclosed herein at a time where such riskexists.

2. Asthma

5-HT (5-hydroxytryptamine) has been linked to the pathophysiology ofacute asthma (see Cazzola, M. and Matera, M. G., TIPS, 2000, 21, 13; andDe Bie, J. J. et al., British J. Pharm., 1998, 124, 857-864). Thecompounds of the present invention disclosed herein are useful in thetreatment of asthma, and the treatment of the symptoms thereof.Accordingly, in some embodiments, the present invention provides methodsfor treating asthma in a patient in need of the treatment, comprisingadministering to the patient a composition comprising a 5-HT_(2A)inverse agonist disclosed herein. In further embodiments, methods areprovided for treating a symptom of asthma in a patient in need of thetreatment, comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein.

3. Agitation

Agitation is a well-recognized behavioral syndrome with a range ofsymptoms, including hostility, extreme excitement, poor impulse control,tension and uncooperativeness (See Cohen-Mansfield J, and Billig, N.,(1986), Agitated Behaviors in the Elderly. I. A Conceptual Review. J AmGeriatr Soc 34(10): 711-721).

Agitation is a common occurrence in the elderly and often associatedwith dementia such as those caused by Alzheimer's disease, Lewy Body,Parkinson's, and Huntington's, which are degenerative diseases of thenervous system and by diseases that affect blood vessels, such asstroke, or multi-infarct dementia, which is caused by multiple strokesin the brain can also induce dementia. Alzheimer's disease accounts forapproximately 50 to 70% of all dementias (See Koss E, et al., (1997),Assessing patterns of agitation in Alzheimer's disease patients with theCohen-Mansfield Agitation Inventory. The Alzheimer's Disease CooperativeStudy Alzheimer Dis Assoc Disord 11(suppl 2):545-S50).

An estimated five percent of people aged 65 and older and up to 20percent of those aged 80 and older are affected by dementia; of thesesufferers, nearly half exhibit behavioral disturbances, such asagitation, wandering and violent outbursts.

Agitated behaviors can also be manifested in cognitively intact elderlypeople and by those with psychiatric disorders other than dementia.

Agitation is often treated with antipsychotic medications such ashaloperidol in nursing home and other assisted care settings. There isemerging evidence that agents acting at the 5-HT_(2A) receptors in thebrain have the effects of reducing agitation in patients, includingAlzheimer's dementia (See Katz, I. R., et al., J Clin Psychiatry 1999February, 60(2):107-115; and Street, J. S., et al., Arch Gen Psychiatry2000 October, 57(10):968-976).

The compounds of the invention disclosed herein are useful for treatingagitation and symptoms thereof. Thus, in some embodiments, the presentinvention provides methods for treating agitation in a patient in needof such treatment comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein. In someembodiments, the agitation is due to a psychiatric disorder other thandementia. In some embodiments, the present invention provides methodsfor treatment of agitation or a symptom thereof in a patient sufferingfrom dementia comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein. In someembodiments of such methods, the dementia is due to a degenerativedisease of the nervous system, for example and without limitation,Alzheimers disease, Lewy Body, Parkinson's disease, and Huntington'sdisease, or dementia due to diseases that affect blood vessels,including, without limitation, stroke and multi-infarct dementia. Insome embodiments, methods are provided for treating agitation or asymptom thereof in a patient in need of such treatment, where thepatient is a cognitively intact elderly patient, comprisingadministering to the patient a composition comprising a 5-HT_(2A)inverse agonist disclosed herein.

4. Add-on Therapy to Haloperidol in the Treatment of Schizophrenia andOther Disorders:

Schizophrenia is a psychopathic disorder of unknown origin, whichusually appears for the first time in early adulthood and is marked by anumber of characteristics, psychotic symptoms, progression, phasicdevelopment and deterioration in social behavior and professionalcapability in the region below the highest level ever attained.Characteristic psychotic symptoms are disorders of thought content(multiple, fragmentary, incoherent, implausible or simply delusionalcontents or ideas of persecution) and of mentality (loss of association,flight of imagination, incoherence up to incomprehensibility), as wellas disorders of perceptibility (hallucinations), of emotions(superficial or inadequate emotions), of self-perception, of intentionsand impulses, of interhuman relationships, and finally psychomotoricdisorders (such as catatonia). Other symptoms are also associated withthis disorder. (See, American Statistical and Diagnostic Handbook).

Haloperidol (Haldol) is a potent dopamine D₂ receptor antagonist. It iswidely prescribed for acute schizophrenic symptoms, and is veryeffective for the positive symptoms of schizophrenia. However, Haldol isnot effective for the negative symptoms of schizophrenia and mayactually induce negative symptoms as well as cognitive dysfunction. Inaccordance with some methods of the invention, adding a 5-HT_(2A)inverse agonist concomitantly with Haldol will provide benefitsincluding the ability to use a lower dose of Haldol without losing itseffects on positive symptoms, while reducing or eliminating itsinductive effects on negative symptoms, and prolonging relapse to thepatient's next schizophrenic event.

Haloperidol is used for treatment of a variety of behavioral disorders,drug induced psychosis, excitative psychosis, Gilles de la Tourette'ssyndrome, manic disorders, psychosis (organic and NOS), psychoticdisorder, psychosis, schizophrenia (acute, chronic and NOS). Furtheruses include in the treatment of infantile autism, huntington's chorea,and nausea and vomiting from chemotherapy and chemotherapeuticantibodies. Administration of 5-HT_(2A) inverse agonists disclosedherein with haloperidol also will provide benefits in these indications.

In some embodiments, the present invention provides methods for treatinga behavioral disorder, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorders, psychosis (organicand NOS), psychotic disorder, psychosis, schizophrenia (acute, chronicand NOS) comprising administering to the patient a dopamine D₂ receptorantagonist and a 5-HT_(2A) inverse agonist disclosed herein.

In some embodiments, the present invention provides methods for treatinga behavioral disorder, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorders, psychosis (organicand NOS), psychotic disorder, psychosis, schizophrenia (acute, chronicand NOS) comprising administering to the patient haloperidol and a5-HT_(2A) inverse agonist disclosed herein.

In some embodiments, the present invention provides methods for treatinginfantile autism, huntington's chorea, or nausea and vomiting fromchemotherapy or chemotherapeutic antibodies comprising administering tothe patient a dopamine D₂ receptor antagonist and a 5-HT_(2A) inverseagonist disclosed herein.

In some embodiments, the present invention provides methods for treatinginfantile autism, huntington's chorea, or nausea and vomiting fromchemotherapy or chemotherapeutic antibodies comprising administering tothe patient haloperidol and a 5-HT_(2A) inverse agonist disclosedherein.

In further embodiments, the present invention provides methods fortreating schizophrenia in a patient in need of the treatment comprisingadministering to the patient a dopamine D₂ receptor antagonist and a5-HT_(2A) inverse agonist disclosed herein. Preferably, the dopamine D₂receptor antagonist is haloperidol.

The administration of the dopamine D₂ receptor antagonist can beconcomitant with administration of the 5-HT_(2A) inverse agonist, orthey can be administered at different times. Those of skill in the artwill easily be able to determine appropriate dosing regimes for the mostefficacious reduction or elimination of deleterious haloperidol effects.In some embodiments, haloperidol and the 5-HT_(2A) inverse agonist areadministered in a single dosage form, and in other embodiments, they areadministered in separate dosage forms.

The present invention further provides methods of alleviating negativesymptoms of schizophrenia induced by the administration of haloperidolto a patient suffering from schizophrenia, comprising administering tothe patient a 5-HT_(2A) inverse agonist as disclosed herein.

5. Sleep Disorders

It is reported in the National Sleep Foundation's 2002 Sleep In AmericaPoll, more than one-half of the adults surveyed (58%) report havingexperienced one or more symptoms of insomnia at least a few nights aweek in the past year. Additionally, about three in ten (35%) say theyhave experienced insomnia-like symptoms every night or almost everynight.

The normal sleep cycle and sleep architecture can be disrupted by avariety of organic causes as well as environmental influences. Accordingto the International Classification of Sleep Disorders, there are over80 recognized sleep disorders. Of these, compounds of the presentinvention are effective, for example, in any one or more of thefollowing sleep disorders (ICSD—International Classification of SleepDisorders: Diagnostic and Coding Manual. Diagnostic ClassificationSteering Committee, American Sleep Disorders Association, 1990):

A. Dyssomnias

a. Intrinsic Sleep Disorders:

Psychophysiological insomnia, Sleep state misperception, Idiopathicinsomnia, Obstructive sleep apnea syndrome, Central sleep apneasyndrome, Central alveolar hypoventilation syndrome, Periodic limbmovement disorder, Restless leg syndrome and Intrinsic sleep disorderNOS.

b. Extrinsic Sleep Disorders:

Inadequate sleep hygiene, Environmental sleep disorder, Altitudeinsomnia, Adjustment sleep disorder, Insufficient sleep syndrome,Limit-setting sleep disorder, SleepOnset association disorder, Nocturnaleating (drinking) syndrome, Hypnotic dependent sleep disorder,Stimulant-dependent sleep disorder, Alcohol-dependent sleep disorder,Toxin-induced sleep disorder and Extrinsic sleep disorder NOS.

c. Circadian Rhythm Sleep Disorders:

Time zone change (jet lag) syndrome, Shift work sleep disorder,Irregular sleep-wake pattern, Delayed sleep phase syndrome, Advancedsleep phase syndrome, Non-24-hour sleep-wake disorder and Circadianrhythm sleep disorder NOS.

B. Parasomnias

a. Arousal Disorders:

Confusional arousals, Sleepwalking and Sleep terrors.

b. Sleep-Wake Transition Disorders:

Rhythmic movement disorder, Sleep starts, Sleep talking and Nocturnalleg cramps.

C. Sleep Disorders Associated with Medical/Psychiatric Disorders

a. Associated with Mental Disorders:

Psychoses, Mood disorders, Anxiety disorders, Panic disorders andAlcoholism.

b. Associated with Neurological Disorders:

Cerebral degenerative disorders, Dementia, Parkinsonism, Fatal familialinsomnia, Sleep-related epilepsy, Electrical status epilepticus of sleepand Sleep-related headaches.

c. Associated with Other Medical Disorders:

Sleeping sickness, Nocturnal cardiac ischemia, Chronic obstructivepulmonary disease, Sleep-related asthma, Sleep-related gastroesophagealreflux, Peptic ulcer disease, Fibrositis syndrome, Osteoarthritis,Rheumatoid arthritis, Fibromyalgia and Post-surgical.

The effects of sleep deprivation are more than excessive daytimesleepiness. Chronic insomniacs report elevated levels of stress,anxiety, depression and medical illnesses (National Institutes ofHealth, National Heart, Lung, and Blood Institute, Insomnia Facts Sheet,October 1995). Preliminary evidence suggests that having a sleepdisorder that causes significant loss of sleep may contribute toincreased susceptibility to infections due to immunosuppression,cardiovascular complications such as hypertension, cardiac arrhythmias,stroke, and myocardial infarction, comprimised glucose tolerance,increased obesity and metabolic syndrome. Compounds of the presentinvention are useful to prevent or alleviate these complications byimproving sleep quality.

The most common class of medications for the majority of sleep disordersare the benzodiazepines, but the adverse effect profile ofbenzodiazepines include daytime sedation, diminished motor coordination,and cognitive impairments. Furthermore, the National Institutes ofHealth Consensus conference on Sleeping Pills and Insomnia in 1984 havedeveloped guidelines discouraging the use of such sedative-hypnoticsbeyond 4-6 weeks because of concerns raised over drug misuse,dependency, withdrawal and rebound insomnia. Therefore, it is desirableto have a pharmacological agent for the treatment of insomnia, which ismore effective and/or has fewer side effects than those currently used.In addition, benzodiazepines are used to induce sleep, but have littleto no effect on the maintenance of sleep, sleep consolidation or slowwave sleep. Therefore, sleep maintenance disorders are not currentlywell treated.

Clinical studies with agents of a similar mechanism of action as arecompounds of the present invention have demonstrated significantimprovements on objective and subjective sleep parameters in normal,healthy volunteers as well as patients with sleep disorders and mooddisorders [Sharpley A L, et al. Slow Wave Sleep in Humans: Role of5-HT_(2A) and SHT_(2C) Receptors. Neuropharmacology, 1994, Vol.33(3/4):467-71; Winokur A, et al. Acute Effects of Mirtazapine on SleepContinuity and Sleep Architecture in Depressed Patients: A Pilot Study.Soc of Biol Psych, 2000, Vol. 48:75-78; and Landolt H P, et al.Serotonin-2 Receptors and Human Sleep: Effect of Selective Antagonist onEEG Power Spectra. Neuropsychopharmacology, 1999, Vol. 21(3):455-66].

Some sleep disorders are sometimes found in conjunction with otherconditions and accordingly those conditions are treatable by compoundsof Formula (Ia). For example, but not limited to, patients sufferingfrom mood disorders typically suffer from a sleep disorder that can betreatable by compounds of Formula (Ia). Having one pharmacological agentwhich treats two or more existing or potential conditions, as does thepresent invention, is more cost effective, leads to better complianceand has fewer side effects than taking two or more agents.

It is an object of the present invention to provide a therapeutic agentfor the use in treating Sleep Disorders. It is another object of thepresent invention to provide one pharmaceutical agent, which may beuseful in treating two or more conditions wherein one of the conditionsis a sleep disorder. Compounds of the present invention described hereinmay be used alone or in combination with a mild sleep inducer (i.e.antihistamine).

Sleep Architecture:

Sleep comprises two physiological states: Non rapid eye movement (NREM)and rapid eye movement (REM) sleep. NREM sleep consists of four stages,each of which is characterized by progressively slower brain wavepatterns, with the slower patterns indicating deeper sleep. So calleddelta sleep, stages 3 and 4 of NREM sleep, is the deepest and mostrefreshing type of sleep. Many patients with sleep disorders are unableto adequately achieve the restorative sleep of stages 3 and 4. Inclinical terms, patients' sleep patterns are described as fragmented,meaning the patient spends a lot of time alternating between stages 1and 2 (semi-wakefulness) and being awake and very little time in deepsleep. As used herein, the term “fragmented sleep architecture” means anindividual, such as a sleep disorder patient, spends the majority oftheir sleep time in NREM sleep stages 1 and 2, lighter periods of sleepfrom which the individual can be easily aroused to a Waking state bylimited external stimuli. As a result, the individual cycles throughfrequent bouts of light sleep interrupted by frequent awakeningsthroughout the sleep period. Many sleep disorders are characterized by afragmented sleep architecture. For example, many elderly patients withsleep complaints have difficulty achieving long bouts of deep refreshingsleep (NREM stages 3 and 4) and instead spend the majority of theirsleep time in NREM sleep stages 1 and 2.

In contrast to fragmented sleep architecture, as used herein the term“sleep consolidation” means a state in which the number of NREM sleepbouts, particularly Stages 3 and 4, and the length of those sleep boutsare increased, while the number and length of waking bouts aredecreased. In essence, the architecture of the sleep disorder patient isconsolidated to a sleeping state with increased periods of sleep andfewer awakenings during the night and more time is spent in slow wavesleep (Stages 3 and 4) with fewer oscillation Stage 1 and 2 sleep.Compounds of the present invention can be effective in consolidatingsleep patterns so that the patient with previously fragmented sleep cannow achieve restorative, delta-wave sleep for longer, more consistentperiods of time.

As sleep moves from stage 1 into later stages, heart rate and bloodpressure drop, metabolic rate and glucose consumption fall, and musclesrelax. In normal sleep architecture, NREM sleep makes up about 75% oftotal sleep time; stage 1 accounting for 5-10% of total sleep time,stage 2 for about 45-50%, stage 3 approximately 12%, and stage 4 13-15%.About 90 minutes after sleep onset, NREM sleep gives way to the firstREM sleep episode of the night. REM makes up approximately 25% of totalsleep time. In contrast to NREM sleep, REM sleep is characterized byhigh pulse, respiration, and blood pressure, as well as otherphysiological patterns similar to those seen in the active waking stage.Hence, REM sleep is also known as “paradoxical sleep.” Sleep onsetoccurs during NREM sleep and takes 10-20 minutes in healthy youngadults. The four stages of NREM sleep together with a REM phase form onecomplete sleep cycle that is repeated throughout the duration of sleep,usually four or five times. The cyclical nature of sleep is regular andreliable; a REM period occurs about every 90 minutes during the night.However, the first REM period tends to be the shortest, often lastingless than 10 minutes, whereas the later REM periods may last up to 40minutes. With aging, the time between retiring and sleep onset increasesand the total amount of night-time sleep decreases because of changes insleep architecture that impair sleep maintenance as well as sleepquality. Both NREM (particularly stages 3 and 4) and REM sleep arereduced. However, stage 1 NREM sleep, which is the lightest sleep,increases with age.

As used herein, the term “delta power” means a measure of the durationof EEG activity in the 0.5 to 3.5 Hz range during NREM sleep and isthought to be a measure of deeper, more refreshing sleep. Delta power ishypothesized to be a measure of a theoretical process called Process Sand is thought to be inversely related to the amount of sleep anindividual experiences during a given sleep period. Sleep is controlledby homeostatic mechanisms; therefore, the less one sleeps the greaterthe drive to sleep. It is believed that Process S builds throughout thewake period and is discharged most efficiently during delta power sleep.Delta power is a measure of the magnitude of Process S prior to thesleep period. The longer one stays awake, the greater Process S or driveto sleep and thus the greater the delta power during NREM sleep.However, individuals with sleep disorders have difficulty achieving andmaintaining delta wave sleep, and thus have a large build-up of ProcessS with limited ability to discharge this buildup during sleep. 5-HT_(2A)agonists tested preclinically and clinically mimic the effect of sleepdeprivation on delta power, suggesting that subjects with sleepdisorders treated with a 5-HT_(2A) inverse agonist or antagonist will beable to achieve deeper more refreshing sleep. These same effects havenot been observed with currently marketed pharmacotherapies. Inaddition, currently marketed pharmacotherapies for sleep have sideeffects such as hangover effects or addiction that are associated withthe GABA receptor. 5-HT_(2A) inverse agonists do not target the GABAreceptor and so these side effects are not a concern.

Subjective and Objective Determinations of Sleep Disorders:

There are a number of ways to determine whether the onset, duration orquality of sleep (e.g. non-restorative or restorative sleep) is impairedor improved. One method is a subjective determination of the patient,e.g., do they feel drowsy or rested upon waking. Other methods involvethe observation of the patient by another during sleep, e.g., how longit takes the patient to fall asleep, how many times does the patientwake up during the night, how restless is the patient during sleep, etc.Another method is to objectively measure the stages of sleep usingpolysomnography.

Polysomnography is the monitoring of multiple electrophysiologicalparameters during sleep and generally includes measurement of EEGactivity, electroculographic activity and electromyographic activity, aswell as other measurements. These results, along with observations, canmeasure not only sleep latency (the amount of time required to fallasleep), but also sleep continuity (overall balance of sleep andwakefulness) and sleep consolidation (percent of sleeping time spent indelta-wave or restorative sleep) which may be an indication of thequality of sleep.

There are five distinct sleep stages, which can be measured bypolysomnography: rapid eye movement (REM) sleep and four stages ofnon-rapid eye movement (NREM) sleep (stages 1, 2, 3 and 4). Stage 1 NREMsleep is a transition from wakefulness to sleep and occupies about 5% oftime spent asleep in healthy adults. Stage 2 NREM sleep, which ischaracterized by specific EEG waveforms (sleep spindles and Kcomplexes), occupies about 50% of time spent asleep. Stages 3 and 4 NREMsleep (also known collectively as slow-wave sleep and delta-wave sleep)are the deepest levels of sleep and occupy about 10-20% of sleep time.REM sleep, during which the majority of vivid dreams occur, occupiesabout 20-25% of total sleep.

These sleep stages have a characteristic temporal organization acrossthe night. NREM stages 3 and 4 tend to occur in the first one-third toone-half of the night and increase in duration in response to sleepdeprivation. REM sleep occurs cyclically through the night. Alternatingwith NREM sleep about every 80-100 minutes. REM sleep periods increasein duration toward the morning. Human sleep also variescharacteristically across the life span. After relative stability withlarge amounts of slow-wave sleep in childhood and early adolescence,sleep continuity and depth deteriorate across the adult age range. Thisdeterioration is reflected by increased wakefulness and stage 1 sleepand decreased stages 3 and 4 sleep.

In addition, the compounds of the invention can be useful for thetreatment of the sleep disorders characterized by excessive daytimesleepiness such as narcolepsy. Inverse agonists at the serotonin5-HT_(2A) receptor improve the quality of sleep at nightime which candecrease excessive daytime sleepiness.

Accordingly, another aspect of the present invention relates to thetherapeutic use of compounds of the present invention for the treatmentof Sleep Disorders. Compounds of the present invention are potentinverse agonists at the serotonin 5-HT_(2A) receptor and can beeffective in the treatment of Sleep Disorders by promoting one or moreof the following: reducing the sleep onset latency period (measure ofsleep induction), reducing the number of nighttime awakenings, andprolonging the amount of time in delta-wave sleep (measure of sleepquality enhancement and sleep consolidation) without effecting REMsleep. In addition, compounds of the present invention can be effectiveeither as a monotherapy or in combination with sleep inducing agents,for example but not limited to, antihistamines.

6. Diabetic-Related Pathologies:

Although hyperglycemia is the major cause for the pathogenesis ofdiabetic complications such as diabetic peripheral neuropathy (DPN),diabetic nephropathy (DN) and diabetic retinopathy (DR), increasedplasma serotonin concentration in diabetic patients has also beenimplicated to play a role in disease progression (Pietraszek, M. H., etal. Thrombosis Res. 1992, 66(6), 765-74; and Andrzejewska-Buczko J, etal., Klin Oczna. 1996; 98(2), 101-4). Serotonin is believed to play arole in vasospasm and increased platelet aggregability. Improvingmicrovascular blood flow is able to benefit diabetic complications.

A recent study by Cameron and Cotter in Naunyn Schmiedebergs ArchPharmacol. 2003 June; 367(6):607-14, used a 5-HT_(2A) antagonistexperimental drug AT-1015, and other non-specific 5-HT_(2A) antagonistsincluding ritanserin and sarpogrelate. These studies found that allthree drugs were able to produce a marked correction (82.6-99.7%) of a19.8% sciatic motor conduction deficit in diabetic rats. Similarly,44.7% and 14.9% reductions in sciatic endoneurial blood flow andsaphenous sensory conduction velocity were completely reversed.

In a separate patient study, sarogrelate was evaluated for theprevention of the development or progression of diabetic nephropathy(Takahashi, T., et al., Diabetes Res Clin Pract. 2002 November;58(2):123-9). In the trial of 24 months of treatment, sarpogrelatesignificantly reduced urinary albumin excretion level.

7. Glaucoma

Topical ocular administration of 5-HT2 receptor antagonists result in adecrease in intra ocular pressure (IOP) in monkeys (Chang et al., J.Ocut Pharmacol 1: 137-147 (1985)) and humans (Mastropasqua et al., ActaOphthalmot Scand Suppl 224:24-25 (1997)) indicating utility for similarcompounds such as 5-HT_(2A) inverse agonists in the treatment of ocularhypertension associated with glaucoma. The 5-HT2 receptor antagonistketanserin (Mastropasqua supra) and sarpogrelate (Takenaka et al.,Investig Ophthalmot V is Sci 36:S734 (1995)) have been shown tosignificantly lower IOP in glaucoma patients.

8. Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a lethaldemyelinating disease caused by an opportunistic viral infection ofoligodendrocytes in immunocompromised patients. The causative agent isJC virus, a ubiquitous papovavirus that infects the majority of thepopulation before adulthood and establishes a latent infection in thekidney. In immunocompromised hosts, the virus can reactivate andproductively infect oligodendrocytes. This previously rare condition,until 1984 reported primarily in persons with underlyinglymphoproliferative disorders, is now more common because it occurs in4% of patients with AIDS. Patients usually present with relentlesslyprogressive focal neurologic defects, such as hemiparesis or visualfield deficits, or with alterations in mental status. On brain MRI, oneor more white matter lesions are present; they are hyperintense onT2-weighted images and hypointense on T1-weighted images. There is nomass effect, and contrast enhancement is rare. Diagnosis can beconfirmed by brain biopsy, with demonstration of virus by in situhybridization or immunocytochemistry. Polymerase chain reactionamplification of JC virus sequences from the CSF can confirm diagnosiswithout the need for biopsy [see, e.g., Antinori et al., Neurology(1997) 48:687-694; Berger and Major, Seminars in Neurology (1999) 19:193-200; and Portegies, et al., Eur. J. Neurol. (2004) 11:297-304].Currently, there is no effective therapy. Survival after diagnosis isabout 3 to 5 months in AIDS patients.

JC virus enters cells by receptor-mediated clathrin-dependentendocytosis. Binding of JC virus to human glial cells (e.g.,oligodendrocytes) induces an intracellular signal that is critical forentry and infection by a ligand-inducible clathrin-dependent mechanism[Querbes et al., J Virology (2004) 78:250-256]. Recently, 5-HT_(2A) wasshown to be the receptor on human glial cells mediating infectious entryof JC virus by clathrin-dependent endocytosis [Elphick et al., Science(2004) 306: 1380-1383]. 5-HT_(2A) antagonists, including ketanserin andritanserin, inhibited JC virus infection of human glial cells.Ketanserin and ritanserin have inverse agonist activity at 5-HT_(2A).

5-HT_(2A) antagonists including inverse agonists have been contemplatedto be useful in the treatment of PML [Elphick et al., Science (2004)306: 1380-1383]. Prophylactic treatment of HIV-infected patients with5-HT_(2A) antagonists is envisioned to prevent the spread of JC virus tothe central nervous system and the development of PML. Aggressivetherapeutic treatment of patients with PML is envisioned to reduce viralspread within the central nervous system and prevent additional episodesof demyelination.

In some embodiments, methods are provided for treating progressivemultifocal leukoencephalopathy in a patient in need of such treatment,comprising administering to the patient a composition comprising a5-HT_(2A) inverse agonist disclosed herein.

9. Hypertension

Serotonin has been observed to play an important role in the regulationof vascular tone, vasoconstriction, and pulmonary hypertension (see,Deuchar, G. et al. Pulm. Pharmacol. Ther. 18(1):23-31. 2005; and Marcos,E. et al. Circ. Res. 94(9):1263-70 2004). Ketanserin, a 5-HT2A inverseagonist, have been demonstrated to protect against circulatory shocks,intracranial hypertension, and cerebral ischemia during heatstroke (see,Chang, C. et al. Shock 24(4): 336-340 2005); and to stabilize bloodpressure in spontaneously hypertensive rats (see, Miao, C. Clin. Exp.Pharmacol. Physiol. 30(3): 189-193). Mainserin, a 5-HT2A inverseagonist, has been shown to prevent DOCA-salt induced hypertension inrats (see, Silva, A. Eur, J. Pharmacol. 518(2-3): 152-7 2005).

10. Pain

5-HT2A inverse agonists are also effective for the treatment of pain.Sarpogrelate has been observed to provide a significant analgesic effectboth on thermal induced pain in rats after intraperitonealadministration and on inflammatory pain in rats after either intrathecalor intraperitoneal administration (see, Nishiyama, T. Eur. J. Pharmacol.516: 18-22 2005). This same 5-HT2A inverse agonist in humans has beenshown to be an effective treatment for lower back pain, leg pain andnumbness associated with sciatica brought on by lumbar disc herniation(see, Kanayama, M. et al. J. Neurosurg:Spine 2:441-446 2005).

Representative Methods of the Invention:

One aspect of the present invention encompasses methods for modulatingthe activity of a 5-HT_(2A) serotonin receptor by contacting thereceptor with a compound according to any of the embodiments describedherein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for thetreatment of platelet aggregation in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for thetreatment of an indication selected from the group consisting ofcoronary artery disease, myocardial infarction, transient ischemicattack, angina, stroke, and atrial fibrillation in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for thetreatment of reducing the risk of blood clot formation in an angioplastyor coronary bypass surgery individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound according to any of the embodiments described herein or apharmaceutical composition.

One aspect of the present invention encompasses methods for thetreatment of reducing the risk of blood clot formation in an individualsuffering from atrial fibrillation, comprising administering to theindividual in need thereof a therapeutically effective amount of acompound according to any of the embodiments described herein or apharmaceutical composition.

One aspect of the present invention encompasses methods for thetreatment of asthma in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound according to any of the embodiments described herein or apharmaceutical composition.

One aspect of the present invention encompasses methods for thetreatment of a symptom of asthma in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for thetreatment of agitation or a symptom thereof in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition. In some embodiments,the individual is a cognitively intact elderly individual.

One aspect of the present invention encompasses methods for thetreatment of agitation or a symptom thereof in an individual sufferingfrom dementia comprising administering to the individual in need thereofa therapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition. In someembodiments, the dementia is due to a degenerative disease of thenervous system. In some embodiments, the dementia is Alzheimers disease,Lewy Body, Parkinson's disease or Huntington's disease. In someembodiments, the dementia is due to diseases that affect blood vessels.In some embodiments, the dementia is due to stroke or multi-infarctdementia.

One aspect of the present invention encompasses methods for thetreatment of an individual suffering from at least one of theindications selected from the group consisting of behavioral disorder,drug induced psychosis, excitative psychosis, Gilles de la Tourette'ssyndrome, manic disorder, organic or NOS psychosis, psychotic disorder,psychosis, acute schizophrenia, chronic schizophrenia and NOSschizophrenia comprising administering to the individual in need thereofa therapeutically effective amount of a dopamine D₂ receptor antagonistand a compound according to any of the embodiments described herein or apharmaceutical composition. In some embodiments, the dopamine D₂receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods for thetreatment of an individual with infantile autism, Huntington's chorea,or nausea and vomiting from chemotherapy or chemotherapeutic antibodiescomprising administering to the individual in need thereof atherapeutically effective amount of a dopamine D₂ receptor antagonistand a compound according to any of the embodiments described herein or apharmaceutical composition. In some embodiments, the dopamine D₂receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods for thetreatment of schizophrenia in an individual comprising administering tothe individual in need thereof a therapeutically effective amount of adopamine D₂ receptor antagonist and a compound according to any of theembodiments described herein or a pharmaceutical composition. In someembodiments, the dopamine D₂ receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods for thetreatment of alleviating negative symptoms of schizophrenia induced bythe administration of haloperidol to an individual suffering from theschizophrenia, comprising administering to the individual in needthereof a therapeutically effective amount of a compound according toany of the embodiments described herein or a pharmaceutical composition.In some embodiments, the haloperidol and the compound or pharmaceuticalcomposition are administered in separate dosage forms. In someembodiments, the haloperidol and the compound or pharmaceuticalcomposition are administered in a single dosage form.

One aspect of the present invention encompasses methods for thetreatment of a sleep disorder in an individual comprising administeringto the individual in need thereof a therapeutically effective amount ofa compound according to any of the embodiments described herein or apharmaceutical composition.

In some embodiments, the sleep disorder is a dyssomnia. In someembodiments, the dyssomnia is selected from the group consisting ofpsychophysiological insomnia, sleep state misperception, idiopathicinsomnia, obstructive sleep apnea syndrome, central sleep apneasyndrome, central alveolar hypoventilation syndrome, periodic limbmovement disorder, restless leg syndrome, inadequate sleep hygiene,environmental sleep disorder, altitude insomnia, adjustment sleepdisorder, insufficient sleep syndrome, limit-setting sleep disorder,sleep-onset association disorder, nocturnal eating or drinking syndrome,hypnotic dependent sleep disorder, stimulant-dependent sleep disorder,alcohol-dependent sleep disorder, toxin-induced sleep disorder, timezone change (jet lag) syndrome, shift work sleep disorder, irregularsleep-wake pattern, delayed sleep phase syndrome, advanced sleep phasesyndrome, and non-24-hour sleep-wake disorder.

In some embodiments, the sleep disorder is a parasomnia. In someembodiments, the parasomnia is selected from the group consisting ofconfusional arousals, sleepwalking and sleep terrors, rhythmic movementdisorder, sleep starts, sleep talking and nocturnal leg cramps. In someembodiments, the sleep disorder is characterized by excessive daytimesleepiness such as narcolepsy.

In some embodiments, the sleep disorder is associated with a medical orpsychiatric disorder. In some embodiments, the medical or psychiatricdisorder is selected from the group consisting of psychoses, mooddisorders, anxiety disorders, panic disorders, alcoholism, cerebraldegenerative disorders, dementia, parkinsonism, fatal familial insomnia,sleep-related epilepsy, electrical status epilepticus of sleep,sleep-related headaches, sleeping sickness, nocturnal cardiac ischemia,chronic obstructive pulmonary disease, sleep-related asthma,sleep-related gastroesophageal reflux, peptic ulcer disease, fibrositissyndrome, osteoarthritis, rheumatoid arthritis, fibromyalgia andpost-surgical sleep disorder.

One aspect of the present invention encompasses methods for thetreatment of a diabetic-related disorder in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition.

In some embodiments, the diabetic-related disorder is diabeticperipheral neuropathy.

In some embodiments, the diabetic-related disorder is diabeticnephropathy.

In some embodiments, the diabetic-related disorder is diabeticretinopathy.

One aspect of the present invention encompasses methods for thetreatment of glaucoma or other diseases of the eye with abnormalintraocular pressure.

One aspect of the present invention encompasses methods for thetreatment of progressive multifocal leukoencephalopathy in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition.

In some embodiments, the individual in need thereof has alymphoproliferative disorder. In some embodiments, thelymphoproliferative disorder is leukemia or lymphoma. In someembodiments, the leukemia or lymphoma is chronic lymphocytic leukemia,Hodgkin's disease, or the like.

In some embodiments, the individual in need thereof has amyeloproliferative disorder.

In some embodiments, the individual in need thereof has carcinomatosis.

In some embodiments, the individual in need thereof has a granulomatousor inflammatory disease. In some embodiments, the granulomatous orinflammatory disease is tuberculosis or sarcoidosis.

In some embodiments, the individual in need thereof isimmunocompromised. In some embodiments, the immunocompromised individualhas impaired cellular immunity. In some embodiments, the impairedcellular immunity comprises impaired T-cell immunity.

In some embodiments, the individual in need thereof is infected withHIV. In some embodiments, the HIV-infected individual has a CD4+ cellcount of ≦200/mm³. In some embodiments, the HIV-infected individual hasAIDS. In some embodiments, the HIV-infected individual has AIDS-relatedcomplex (ARC). In certain embodiments, ARC is defined as the presence oftwo successive CD4+ cell counts below 200/mm³ and at least two of thefollowing signs or symptoms: oral hairy leukoplakia, recurrent oralcandidiasis, weight loss of at least 2.5 kg or 10% of body weight withinlast six months, multidermatomal herpes zoster, temperature above 38.5°C. for more than 14 consecutive days or more than 15 days in a 30-dayperiod, or diarrhea with more than three liquid stools per day for atleast 30 days [see, e.g., Yamada et al., Clin. Diagn. Virol. (1993)1:245-256].

In some embodiments, the individual in need thereof is undergoingimmunosuppressive therapy. In some embodiments, the immunosuppressivetherapy comprises administering an immunosuppressive agent [see, e.g.,Mueller, Ann Thorac Surg (2004) 77:354-362; and Krieger and Emre,Pediatr Transplantation (2004) 8:594-599]. In some embodiments, theimmunosuppressive therapy comprises administering an immunosuppressiveagent selected from the group consisting of: corticosteroids (forexample, prednisone and the like), calcineurin inhibitors (for example,cyclosporine, tacrolimus, and the like), antiproliferative agents (forexample, azathioprine, mycophenolate mofetil, sirolimus, everolimus, andthe like), T-cell depleting agents (for example, OKT® 3 monoclonalantibody (mAb), anti-CD3 immunotoxin FN18-CRM9, Campath-1H (anti-CD52)mAb, anti-CD4 mAb, anti-T cell receptor mAb, and the like), anti-IL-2receptor (CD25) mAb (for example, basiliximab, daclizumab, and thelike), inhibitors of co-stimulation (for example, CTLA4-Ig, anti-CD154(CD40 ligand) mAb, and the like), deoxyspergualin and analogs thereof(for example, 15-DSG, LF-08-0299, LF14-0195, and the like), leflunomideand analogs thereof (for example, leflunomide, FK778, FK779, and thelike), FTY720, anti-alpha-4-integrin monoclonal antibody, and anti-CD45RB monoclonal antibody. In some embodiments, the immunosuppressive agentand said compound or pharmaceutical composition are administered inseparate doseage forms. In some embodiments, the immunosuppressive agentand said compound or pharmaceutical composition are administered in asingle doseage form.

In some embodiments, the individual in need thereof is undergoingimmunosuppressive therapy after organ transplantation. In someembodiments, the organ is liver, kidney, lung, heart, or the like [see,e.g., Singh et al., Transplantation (2000) 69:467-472].

In some embodiments, the individual in need thereof is undergoingtreatment for a rheumatic disease. In some embodiments, the rheumaticdisease is systemic lupus erythematosus or the like.

In some embodiments, the compound or the pharmaceutical compositioninhibits JC virus infection of human glial cells.

One aspect of the present invention encompasses processes for preparinga composition comprising admixing a compound according any embodimentsdescribed herein and pharmaceutically acceptable carrier.

One aspect of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is platelet aggregation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is selected from the groupconsisting of coronary artery disease, myocardial infarction, transientischemic attack, angina, stroke, and atrial fibrillation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is a blood clot formation in anangioplasty or coronary bypass surgery individual.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is a blood clot formation in anindividual suffering from atrial fibrillation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is asthma.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is a symptom of asthma.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is agitation or a symptom thereofin an individual. In some embodiments the individual is a cognitivelyintact elderly individual.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is agitation or a symptom thereofin an individual suffering from dementia. In some embodiments thedementia is due to a degenerative disease of the nervous system. In someembodiment the dementia is Alzheimers disease, Lewy Body, Parkinson'sdisease, or Huntington's disease. In some embodiments the dementia isdue to diseases that affect blood vessels. In some embodiments thedementia is due to stroke or multi-infract dementia.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder further comprising a dopamine D₂ receptor antagonistwherein the disorder is selected from the group consisting of abehavioral disorder, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorder, organic or NOSpsychosis, psychotic disorder, psychosis, acute schizophrenia, chronicschizophrenia and NOS schizophrenia. In some embodiments the dopamine D₂receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder further comprising a dopamine D₂ receptor antagonistwherein the disorder is infantile autism, Huntington's chorea, or nauseaand vomiting from chemotherapy or chemotherapeutic antibodies. In someembodiments the dopamine D₂ receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder further comprising a dopamine D₂ receptor antagonistwherein the disorder is schizophrenia. In some embodiments the dopamineD₂ receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is a negative symptom or symptomsof schizophrenia induced by the administration of haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the haloperidol and the compound orpharmaceutical composition are administered in separate dosage forms.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the haloperidol and the compound orpharmaceutical composition are administered in a single dosage form.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)mediated disorder wherein the disorder is progressive multifocalleukoencephalopathy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method of treatment of thehuman or animal body by therapy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method for the treatmentof a 5-HT_(2A) mediated disorder, as described herein, in the human oranimal body by therapy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method for the treatmentof a sleep disorder, as described herein, in the human or animal body bytherapy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method for the treatmentof platelet aggregation in the human or animal body by therapy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method for the treatmentof progressive multifocal leukoencephalopathy in the human or animalbody by therapy.

Pharmaceutical Compositions

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more compounds as described herein andone or more pharmaceutically acceptable carriers. Some embodimentspertain to pharmaceutical compositions comprising a compound of thepresent invention and a pharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions, and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants, and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions, and syrups. Alternatively, the oral preparationsmay be in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives, and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampoule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20th Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro, A. R., et al.).

While it is possible that, for use in the treatment, a compound of theinvention may, in an alternative use, be administered as a raw or purechemical, it is preferable however to present the compound or activeingredient as a pharmaceutical formulation or composition furthercomprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers thereof and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not overly deleterious tothe recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with a minimum of degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a solvate or physiologicallyfunctional derivative thereof can be used as active ingredients inpharmaceutical compositions, specifically as 5-HT_(2A) receptormodulators. By the term “active ingredient” is defined in the context ofa “pharmaceutical composition” and shall mean a component of apharmaceutical composition that provides the primary pharmacologicaleffect, as opposed to an “inactive ingredient” which would generally berecognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can varywithin wide limits, as is customary and is known to the physician, it isto be tailored to the individual conditions in each individual case. Itdepends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention. Representative dosesof the present invention include, but are not limited to, about 0.001 mgto about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg toabout 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg toabout 25 mg. Multiple doses may be administered during the day,especially when relatively large amounts are deemed to be needed, forexample 2, 3 or 4, doses. Depending on the individual and as deemedappropriate from the patient's physician or caregiver it may benecessary to deviate upward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, or whether anacute or chronic disease state is being treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions of this invention is selected inaccordance with a variety factors as cited above. Thus, the actualdosage regimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimen outside these typical ranges can be testedand, where appropriate, may be used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4, part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavouringagents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5 to about 90 percent of the active compound; however, anartisan would know when amounts outside of this range are necessary.Suitable carriers for powders and tablets are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets, and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavours, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of thepresent invention or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the present invention as an aerosol can be prepared byprocesses well-known to the person skilled in the art. For theirpreparation, for example, solutions or dispersions of the compounds ofthe present invention in water, water/alcohol mixtures or suitablesaline solutions can be employed using customary additives, for examplebenzyl alcohol or other suitable preservatives, absorption enhancers forincreasing the bioavailability, solubilizers, dispersants and others,and, if appropriate, customary propellants, for example include carbondioxide, CFC's, such as, dichlorodifluoromethane,trichlorofluoromethane, or dichlorotetrafluoroethane; and the like. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric,tartaric, oxalic, p-toluenesulfonic and the like, such as thosepharmaceutically acceptable salts listed in Journal of PharmaceuticalScience, 66, 2 (1977); incorporated herein by reference in its entirety.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Compounds of the present invention can be converted to “pro-drugs.” Theterm “pro-drugs” refers to compounds that have been modified withspecific chemical groups known in the art and when administered into anindividual these groups undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as compounds of the inventioncontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the compound. Inone general aspect, the “pro-drug” approach is utilized to facilitateoral absorption. A thorough discussion is provided in T. Higuchi and V.Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series; and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference in theirentirety.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound according to any of the compoundembodiments disclosed herein, together with at least one knownpharmaceutical agent as described herein and a pharmaceuticallyacceptable carrier.

It is noted that when the 5-HT_(2A) receptor modulators are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as 5-HT_(2A)receptor modulators, for the treatment of a 5-HT_(2A) mediated diseaseor disorder in domestic animals (e.g., cats and dogs) and in otherdomestic animals (e.g., such as cows, chickens, fish, etc.). Those ofordinary skill in the art are readily credited with understanding theutility of such compounds in such settings.

Combination Therapy:

While the compounds of the present invention can be administered as thesole active pharmaceutical agent (i.e., mono-therapy), they can also beused in combination with other pharmaceutical agents (i.e.,combination-therapy) for the treatment of thediseases/conditions/disorders described herein. Accordingly, anotheraspect of the present invention includes methods of treatment of5-HT_(2A) serotonin receptor mediated disorders diseases comprisingadministering to an individual in need of such treatment atherapeutically-effective amount of a compound of the present inventionin combination with one or more additional pharmaceutical agent asdescribed herein.

Suitable pharmaceutical agents that can be used in combination with thecompounds of the present invention include other antiplatelet,antithrombotic or anticoagulant drugs, anti-arrhythmic agents,Cholesteryl ester transfer protein (CETP) inhibitors, Niacin or niacinanalogs, Adenosine or adenosine analogs, Nitroglycerin or nitrates,prothrombolytic agents, and the like. Other pharmaceutical agents,including the agents set forth infra, are well known or will be readilyapparent in light of the instant disclosure, to one of ordinary skill inthe art.

The compounds of the present invention can also be used in combinationwith other antiplatelet, antithrombotic or anticoagulant drugs such asthrombin inhibitors, platelet aggregation inhibitors such as aspirin,clopidogrel (Plavix®), ticlopidine or CS-747 {i.e., acetic acid5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-ylester and its active metabolite R-99224,(Z)-2-[1-[2-cyclopropyl-1(S)-(2-fluorophenyl)-2-oxoethyl]-4(R)-sulfanylpiperidin-3-ylidene]aceticacid}, abciximab (ReoPro®), eptifibatide (Integrilin®), tirofiban(Aggrastat®), warfarin, low molecular weight heparins (such as LOVENOX),GPIIb/GPIIIa blockers, PAI-1 inhibitors such as XR-330 [i.e., (3Z,6Z)-3-Benzylidene-6-(4-methoxybenzylidene)-1-methylpiperazine-2,5-dione]and T-686 [i.e., 3(E)-Benzylidene-4(E)-(3,4,5-trimethoxybenzylidene)pyrrolidine-2,5-dione],inhibitors of α-2-antiplasmin such as anti-α-2-antiplasmin antibody andthromboxane receptor antagonists (such as ifetroban), prostacyclinmimetics, phosphodiesterase (PDE) inhibitors, such as dipyridamole(Persantine®) or cilostazol, PDE inhibitors in combination withthromboxane receptor antagonists/thromboxane A synthetase inhibitors(such as picotamide), serotonin-2-receptor antagonists (such asketanserin), fibrinogen receptor antagonists, hypolipidemic agents, suchas HMG-CoA reductase inhibitors, e.g., pravastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, AZ4522, and itavastatin(Nissan/Kowa); microsomal triglyceride transport protein inhibitors(such as disclosed in U.S. Pat. Nos. 5,739,135, 5,712,279 and5,760,246), antihypertensive agents such as angiotensin-convertingenzyme inhibitors (e.g., captopril, lisinopril or fosinopril);angiotensin-II receptor antagonists (e.g., irbesartan, losartan orvalsartan); and/or ACE/NEP inhibitors (e.g., omapatrilat andgemopatrilat); β-blockers (such as propranolol, nadolol and carvedilol),PDE inhibitors in combination with aspirin, ifetroban, picotamide,ketanserin, or clopidogrel (Plavix®) and the like.

The compound of the present invention can also be used in combinationwith anti-arrhythmic agents such as for atrial fibrillation, forexample, amiodarone or dofetilide.

The compound of the present invention can also be used in combinationwith Cholesteryl ester transfer protein (CETP) inhibitors fordislipidemia and atherosclerosis, Niacin or niacin analogs fordislipidemia and atherosclerosis, Adenosine or adenosine analogs forvasodilation, Nitroglycerin or nitrates for vasodilation.

The compounds of the present invention can be used in combination withprothrombolytic agents, such as tissue plasminogen activator (natural orrecombinant), streptokinase, reteplase, activase, lanoteplase,urokinase, prourokinase, anisolated streptokinase plasminogen activatorcomplex (ASPAC), animal salivary gland plasminogen activators, and thelike. The compounds of the present invention may also be used incombination with β-adrenergic agonists such as albuterol, terbutaline,formoterol, salmeterol, bitolterol, pilbuterol, or fenoterol;anticholinergics such as ipratropium bromide; anti-inflammatorycortiocosteroids such as beclomethasone, triamcinolone, budesonide,fluticasone, flunisolide or dexamethasone; and anti-inflammatory agentssuch as cromolyn, nedocromil, theophylline, zileuton, zafirlukast,monteleukast and pranleukast.

Suitable pharmaceutical agents that can be used in combination withcompounds of the present invention include antiretrovirals [see, e.g.,Turpin, Expert Rev Anti Infect Ther (2003) 1:97-128]. Some embodimentsof the present invention include methods of treatment of progressivemultifocal leukoencephalopathy as described herein comprisingadministering to an individual in need of such treatment atherapeutically effective amount or dose of a compound of the presentinvention in combination with at least one pharmaceutical agent selectedfrom the group consisting of: nucleoside reverse transcriptaseinhibitors (for example, Retrovir®, Epivir®, Combivir®, Hivid®, Videx®,Trizvir®, Zerit®, Ziagen®, Vired®, Emtricitabine, DAPD, and the like),non-nucleoside reverse transcriptase inhibitors (for example,Virammune®, Rescriptor®, Sustiva®, GW687, DPC083, TMC 125, Emivirine,Capravirine, BMS 561390, UC-781 and other oxathiin carboxyanilides,SJ-3366, Alkenyldiarylmethane (ADAM), Tivirapine, Calanolide A, HBY097,Loviride, HEPT Family Derivatives, TIBO Derivatives, and the like),protease inhibitors (for example, Fortovase®, Invirase®, Novir®,Crixivan®, Viracep®, Ageberase®, Kaletra®, Atazanavir, Tipranavir,DMP450, and the like), inhibitors of HIV-cell interaction (for example,soluble CD4, toxin-conjugated CD4, monoclonal antibodies to CD4 orgp120, PRO 542, dextran sulfate, Rersobene, FP-23199, Cyanovirin-N,Zintevir (T30177, AR177), L-chicoric acid and derivatives, and thelike), coreceptor inhibitors ligands (for example, R5, X4, modifiedligands (R5), modified ligands (X4), and the like), coreceptorinhibitors X4 (for example, T22, T134, ALX40-4C, AMD3100, bycyclamderivatives, and the like), coreceptor inhibitors R5 (for example,TAK-779, SCH-C(SCH-351125), SCH-D (SCH-350634), NSC 651016, ONOPharmaceutical, Merck, and the like), fusion inhibitors (for example,Fuzeon® (T-20, DP 178, enfuvritide) trimeris, T-1249, TMC125, and thelike), integrase inhibitors (for example, 5CITEP, L731,988, L708,906,L-870,812, S-1360, and the like), NCp7 nucleocapsid Zn finger inhibitors(for example, NOBA, DIBA, dithianes, PD-161374, pyridinioalkanoylthioesters (PATES), azodicarbonamide (ADA), cyclic 2,2 dithiobisbenzamide, and the like), RNase H inhibitors (for example, BBHN, CPHMPD-26388, and the like), Tat inhibitors (for example, dominant negativemutants, Ro24-7429, Ro5-3335, and the like), Rev inhibitors (forexample, dominant negative mutants, Leptomycin B, PKF050-638, and thelike), transcriptional inhibitors (for example, Temacrazine, K-12 andK-37, EM2487, and the like), inhibitors of HIV assembly/maturation (forexample, CAP-1 and CAP-2, and the like), and pharmaceutical agentsdirected to cellular anti-HIV targets (for example, LB6-B275 andHRM1275, Cdk9 inhibitors, and the like).

In a certain embodiment, a compound of the invention can be used inconjunction with highly active antiretroviral therapy (HAART). Whenantiretroviral drugs are used in combinations of three or four drugs,this treatment is called HAART [see, e.g., Portegies, et al., Eur. J.Neurol. (2004) 11:297-304].

In accordance with the present invention, the combination of a compoundof the present invention and pharmaceutical agent can be prepared bymixing the respective active components either all together orindependently with a pharmaceutically acceptable carrier, excipient,binder, diluent, etc. as described herein, and administering the mixtureor mixtures either orally or non-orally as a pharmaceuticalcomposition(s). When a compound or a mixture of compounds of Formula(Ia) are administered as a combination therapy with another activecompound each can be formulated as separate pharmaceutical compositionsgiven at the same time or at different times. Alternatively, in someembodiments, pharmaceutical compositions of the present inventioncomprise a compound or a mixture of compounds of Formula (Ia) and thepharmaceutical agent(s) as a single pharmaceutical composition.

Other Utilities

Another object of the present invention relates to radio-labeledcompounds of the present invention that would be useful not only inradio-imaging but also in assays, both in vitro and in vivo, forlocalizing and quantitating the 5-HT_(2A) receptor in tissue samples,including human, and for identifying 5-HT_(2A) receptor ligands byinhibition binding of a radio-labeled compound. It is a further objectof this invention to develop novel 5-HT_(2A) receptor assays of whichcomprise such radio-labeled compounds.

The present invention embraces isotopically-labeled compounds of thepresent invention. An “isotopically” or “radio-labeled” compounds arethose which are identical to compounds disclosed herein, but for thefact that one or more atoms are replaced or substituted by an atomhaving an atomic mass or mass number different from the atomic mass ormass number typically found in nature (i.e., naturally occurring).Suitable radionuclides that may be incorporated in compounds of thepresent invention include, but are not limited to, ²H (also written as Dfor deuterium), ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N,¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I,¹²⁵I, and ¹³¹I. The radionuclide that is incorporated in the instantradio-labeled compounds will depend on the specific application of thatradio-labeled compound. For example, for in vitro 5-HT_(2A) receptorlabeling and competition assays, compounds that incorporate ³H, ¹⁴C,⁸²Br, ¹²⁵I, ¹³¹I ³⁵S or will generally be most useful. For radio-imagingapplications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br willgenerally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound of Formula (Ia) that has incorporated at least oneradionuclide; in some embodiments the radionuclide is selected from thegroup consisting of ³H ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Certain isotopically-labeled compounds of the present invention areuseful in compound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Schemes supra and Examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or the more scarce radio-isotope ornonradio-active isotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. These synthetic methods, for example, incorporatingactivity levels of tritium into target molecules, are as follows:

A. Catalytic Reduction with Tritium Gas—This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]—This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters, and the like.

C. Reduction with Lithium Aluminum Hydride [³H]—This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters, and the like.

D. Tritium Gas Exposure Labeling—This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]—This procedure is usuallyemployed to prepare O-methyl or N-methyl (³H) products by treatingappropriate precursors with high specific activity methyl iodide (³H).This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include:

A. Sandmeyer and like reactions—This procedure transforms an aryl orheteroaryl amine into a diazonium salt, such as a tetrafluoroboratesalt, and subsequently to ¹²⁵I labeled compound using Na¹²⁵I. Arepresented procedure was reported by Zhu, D.-G. and co-workers in J.Org. Chem. 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols—This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labeled Compd Radiopharm. 1999, 42,S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I—This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkyltinintermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)4]or through an aryl or heteroaryl lithium, in the presence of atri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃]. Arepresented procedure was reported by Bas, M.-D. and co-workers in J.Labeled Compd Radiopharm. 2001, 44, S280-S282.

A radio-labeled 5-HT_(2A) receptor compound of Formula (Ia) can be usedin a screening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radio-labeledcompound of Formula (Ia)” to the 5-HT_(2A) receptor. Accordingly, theability of a test compound to compete with the “radio-labeled compoundof Formula (Ia)” for the binding to the 5-HT_(2A) receptor directlycorrelates to its binding affinity.

The labeled compounds of the present invention bind to the 5-HT_(2A)receptor. In one embodiment the labeled compound has an IC₅₀ less thanabout 500 μM, in another embodiment the labeled compound has an IC₅₀less than about 100 μM, in yet another embodiment the labeled compoundhas an IC₅₀ less than about 10 μM, in yet another embodiment the labeledcompound has an IC₅₀ less than about 1 μM, and in still yet anotherembodiment the labeled inhibitor has an IC₅₀ less than about 0.1 μM.

Other uses of the disclosed receptors and methods will become apparentto those in the art based upon, inter alia, a review of this disclosure.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages, and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Example 1 Syntheses of Compounds of the Present Invention

Illustrated syntheses for compounds of the present invention are shownin FIG. 1 through 12 where the symbols have the same definitions as usedthroughout this disclosure.

The compounds of the invention and their synthesis are furtherillustrated by the following examples. The following examples areprovided to further define the invention without, however, limiting theinvention to the particulars of these examples. The compounds describedherein, supra and infra, are named according to CS Chem Draw UltraVersion 7.0.1 or AutoNom 2000. In certain instances common names areused and it is understood that these common names would be recognized bythose skilled in the art.

Chemistry:

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded on aVarian Mercury Vx-400 equipped with a 4 nucleus auto switchable probeand z-gradient or a Bruker Avance-400 or 500 MHzequipped with a QNP(Quad Nucleus Probe) or a BBI (Broad Band Inverse) and z-gradient.Chemical shifts are given in parts per million (ppm) with the residualsolvent signal used as reference. NMR abbreviations are used as follows:s=singlet, d=doublet, dd=doublet of doublet, dt=doublet of triplet,t=triplet, q=quartet, m=multiplet, br=broad. Microwave irradiations werecarried out using the Emrys Synthesizer (Personal Chemistry). Thin-layerchromatography (TLC) was performed on silica gel 60 F₂₅₄ (Merck),preparatory thin-layer chromatography (prep TLC) was preformed on PK6Fsilica gel 60 A 1 mm plates (Whatman), and column chromatography wascarried out on a silica gel column using Kieselgel 60, 0.063-0.200 mm(Merck). Evaporation was done in vacuo on a Buchi rotary evaporator.Celite 545® was used during palladium filtrations.

LCMS specs: 1) PC: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC systemcontroller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, ShimadzuInc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.2) Mac: HPLC-pumps: LC-8A VP, Shimadzu Inc; HPLC system controller:SCL-10A VP, Shimadzu Inc.

UV-Detector: SPD-10A VP, Shimadzu Inc; Autosampler: 215 Liquid Handler,Gilson Inc; Mass spectrometer: API 150EX with Turbo Ion Spray source,AB/MDS Sciex

Software: Masschrom 1.5.2. Example 1.1 Preparation of1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound 13) Step 1.1a: Preparation of the intermediate1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.Method A

A mixture of1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea(0.270 g, 0.69 mmol) in anhydrous 1,2-dichloroethane (10 mL) was cooledto 0° C. in an ice bath and stirred for 10 minutes. Anhydrous aluminumchloride (0.368 g, 2.76 mmol) was added and the reaction mixture stirredat 0° C. for 20 minutes, then moved to an oil bath and stirred at 80° C.for 1 hour. Ethyl acetate was added and washed with potassium sodiumtartrate (10%) twice. The organic layer was separated, dried overanhydrous Na₂SO₄, filtered and concentrated to give a crude product thatwas subjected to purification on HPLC. The proper fractions werecollected and lyophilized to afford1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas a white solid in 75.0% yield. LCMS m/z (%)=379 (M+H³⁵Cl, 100), 381(M+H³⁷Cl, 40). ¹H NMR (400 MHz, DMSO-d₆) δ 9.81 (s, 1H), 8.92 (s, 1H),8.45 (s, 1H), 8.12-8.06 (m, 1H), 7.63 (s, 1H), 7.40-7.31 (m, 3H),7.09-7.04 (m, 1H), 6.99 (d, J₁=8.72 Hz, 1H), 3.69 (s, 3H).

Step 1.1b: Preparation of1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound 13). Method B

To a solution of1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(0.35 g, 0.09 mmol) in anhydrous THF (2 mL), triphenyl phosphine (70.8mg, 0.27 mmol) and 1-(2-hydroxyethyl)-pyrrolidine (0.032 mL, 0.27 mmol)were added followed by dropwise addition of diisopropyl azodicarboxylate(DIAD) (0.052 mL, 0.27 mmol). The reaction mixture was stirred at roomtemperature for 2 hours, concentrated to give a crude product that wassubjected to purification by preparative HPLC. The proper fractions werecollected, neutralized with 1N NaOH and extracted with EtOAc four times.The solution was evaporated under reduced pressure to afford Compound 13as an off-white solid in 52.8% yield. LCMS m/z (%)=476 (M+H³⁵Cl, 100),478 (M+H³⁷Cl, 40). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.10 (s, 1H), 8.55 (s,1H), 8.17-8.09 (m, 1H), 7.69 (s, 1H), 7.61 (dd, J=8.97 and 2.72 Hz, 1H),7.47 (d, J=2.70 Hz, 1H), 7.43-7.36 (m, 1H), 7.26 (d, J=9.04 Hz, 1H),7.16-7.09 (m, 1H), 4.25-4.08 (m, 2H), 3.73 (s, 3H), 2.58-2.45 (m, 2H),2.45-2.29 (m, 4H), 1.75-1.69 (m, 4H).

Example 1.2 Preparation of the intermediate3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenylamine.Method C

N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetamide(1.0 g, 2.92 mmol) was dissolved in ethanol (15 mL) then aqueous sodiumhydroxide (2.5 mL, 50% w/w) was added and the reaction mixture stirredat 80° C. overnight then concentrated. Water and brine were added thenextracted with EtOAc three times. The organic layers were combined,dried over anhydrous Na₂SO₄ then solvent removed under reduced pressureto afford3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenylamine asa brown oil in 97.1% yield.

LCMS m/z (%)=301 (M+H, 100).

Example 1.3 Preparation of[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-carbamicacid isopropyl ester (Compound 33). Method D

To a solution of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenylamine(30.0 mg, 0.1 mmol) in methylene chloride (1 mL) was added pyridine(24.3 μL, 0.3 mmol). The mixture was treated with isopropylchloroformate (13.3 μL, 0.11 mmol) then the reaction mixture was stirredat room temperature overnight and concentrated to give an oily residuethat was subjected to purification by flash chromatography (SiO₂,CH₂Cl₂/MeOH gradient elution) to afford Compound 33 as an off-white waxysolid in 90.6% yield. LCMS m/z (%)=387 (M+H, 100).

Example 1.4 Preparation ofN-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-2-phenyl-acetamide(Compound 35). Method E

To a solution of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenylamine(21.0 mg, 0.07 mmol) in methylene chloride (1 mL) was added pyridine(17.0 μL, 0.3 mmol). The mixture was treated with phenylacetylchloride(10.6 μL, 0.8 mmol) then the reaction mixture was stirred at roomtemperature overnight and concentrated to give an oily residue that wassubjected to purification by flash chromatography (SiO₂, CH₂Cl₂/MeOHgradient elution) to afford Compound 35 as an off-white solid in 81.2%yield. LCMS m/z (%)=419 (M+H, 100).

Example 1.5 Preparation of1-benzyl-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea(Compound 44). Method F

A solution of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenylamine(21.0 mg, 0.07 mmol) in methylene chloride (1 mL) was treated withbenzyl isocyanate (9.1 μL, 0.074 mmol) then the reaction mixture wasstirred at room temperature overnight and concentrated to give an oilyresidue that was subjected to purification by flash chromatography(SiO₂, CH₂Cl₂/MeOH gradient elution) to afford Compound 44 as anoff-white solid in 51.4% yield. LCMS m/z (%)=434 (M+H, 100). ¹H NMR (400MHz, Acetone-d₆) δ: 8.04 (s, 1H), 7.57 (dd, J=8.88 and 2.70 Hz, 1H),7.48 (d, J=2.67 Hz, 1H), 7.42-7.27 (m, 6H), 7.07 (d, J=8.91 Hz, 1H),6.26 (bs, 1H), 6.23 (d, J=1.8 Hz, 1H), 4.45 (d, J=5.85 Hz, 2H), 4.13 (t,J=5.70 Hz, 1H), 3.77 (s, 3H), 2.70-2.64 (m, 2H), 2.52-2.41 (m, 4H),1.58-1.51 (m, 4H), 1.46-1.38 (m, 2H).

Example 1.6 Preparation of1-{2-[4-[3-(2,4-difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid methyl ester (Compound 125) Step 1.6a: Preparation of1-{2-[2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid methyl ester. Method G

To 5-[2-(2-bromo-ethoxy)-5-nitro-phenyl]-1-methyl-1H-pyrazole (200.0 mg,0.61 mmol) in acetonitrile (3 mL), was added DIEA followed by additionof the H-DL-Pro-OMe. The reaction mixture was heated with microwaves at170° C. for 20 min then subjected to purification by prep HPLC. Theproper fractions were collected and lyophilized to afford atrifluoroacetic acid salt of1-{2-[2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid methyl ester as a light brown oil in 84.2% yield. LCMS m/z (%)=375(M+H, 100).

Step 1.6b: Preparation of1-{2-[4-amino-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid methyl ester. Method H

1-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid methyl ester (150.0 mg) in methanol (15 mL) was treated with acatalytic amount of palladium on activated carbon (10 wt %, Degussa),degassed with argon then hydrogen from a balloon was allowed to bubblethrough the slurry at room temperature overnight. The reaction mixturewas filtered through Celite. The filtrate was concentrated under reducedpressureand dried to afford a trifluoroacetic acid salt of1-{2-[4-amino-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-pyrrolidine-2-carboxylicacid methyl ester as a brown oil in 92% yield. LCMS m/z (%)=345 (M+H,100).

Step 1.6c: Preparation of1-{2-[4-[3-(2,4-difluoro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]ethyl}-pyrrolidine-2-carboxylicacid methyl ester (Compound 125)

The title compound was prepared in a similar manner as described inMethod F to give a colorless oil. LCMS m/z (%)=500 (M+H, 100).

Example 1.7 Preparation of(1H-benzoimidazol-2-yl)-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]amine(Compound 196). Method I

To a mixture of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenylamine(0.105 g, 0.28 mmol) and 2-chlorobenzimidazole (0.057 g, 0.33 mmol) inethanol (1 mL) two drops of 1N HCl were added. The reaction mixture washeated with microwaves at 180° C. for 1 hour, concentrated thensubjected to purification by prep HPLC. The proper fractions werecollected and lyophilized to afford Compound 196 as an off-white solidin 17.1% yield. LCMS m/z (%)=495 (M+H⁷⁹Br, 100), 497 (M+H⁸¹Br, 90).

Example 1.8 Preparation of3-(1-{2-[4-[3-(4-chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]ethyl}-piperidin-4-yl)-propionicacid methyl ester (Compound 151). Method J

A mixture of1-[4-(2-chloro-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4-chloro-phenyl)-urea(0.104 g, 0.257 mmol), 3-piperidin-4-yl-propionic acid methyl ester(0.108 g, 0.631 mmol), and potassium carbonate (0.143, 1.03 mmol) in DMA(4.5 mL) was heated with microwave irradiation at 150° C. for 1 hour.The crude mixture was purified by HPLC to afford Compound 151 as an oil(TFA salt, 0.030 g, 18%). Exact mass calculated for C₂₈H₃₄ClN₅O₄ 539.23.found 540.4 (MH⁺). ¹H NMR (400 MHz, chloroform-d₆) δ: 10.70 (s, 1H),8.24-8.30 (m, 2H), 7.61-7.62 (m, 1H), 7.57 (broad s, 1H), 7.34-7.36 (m,2H), 7.20-7.22 (m, 2H), 7.14-7.16 (m, 1H), 6.70-6.71 (m, 1H), 6.23 (s,1H), 4.27 (s, 2H), 3.71 (s, 3H), 3.67 (s, 3H), 3.24-3.31 (m, 2H),3.51-3.57 (m, 2H), 2.24-2.28 (t, J=7.33 Hz, 2H), 1.40-1.75 (m, 8H).

Example 1.9 Preparation of(1-{2-[4-[3-(4-chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]ethyl}-piperidin-3-yl)-aceticacid (Compound 175). Method K

To a stirred solution of(1-{2-[4-[3-(4-chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-3-yl)-aceticacid ethyl ester (TFA salt, 0.038 g, 0.058 mmol) in a mixture of THF(0.9 mL), MeOH (0.3 mL), and H₂O (0.3 mL) was added lithium hydroxide,monohydrate (0.044 g, 1.05 mmol) at room temperature, and the mixturewas stirred for 45 mins. The crude mixture was purified by HPLC toafford Compound 175 as an oil (TFA salt, 0.024 g, 66%). Exact masscalculated for C₂₆H₃₀ClN₅O₄ 511.2. found 512.3 (MH⁺). ¹H NMR (400 MHz,methanol-d₄) δ: 7.39-7.42 (m, 2H), 7.29-7.32 (m, 3H), 7.13-7.15 (m, 2H),7.01-7.03 (m, 1H), 6.23 (s, 1H), 4.23-4.24 (m, 2H), 3.36 (s, 2H), 3.30(s, 1H), 3.18 (s, 3H), 2.58-2.64 (m, 2H), 2.46-2.52 (m, 2H), 2.10-2.15(m, 2H), 2.03-2.06 (m, 1H), 1.71 (s br, 2H), 1.54-1.57 (m, 1H),1.01-1.04 (m, 1H).

Example 1.10 Preparation of4-(4-{2-[4-[3-(4-chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]ethyl}-piperazin-1-yl)-4-oxo-butyricacid methyl ester (Compound 176). Method L

To a stirred solution of1-(4-chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperazin-1-yl-ethoxy)-phenyl]-urea(HCl salt, 0.033 g, 0.067 mmol) and DIEA (0.035 g, 46 μL, 0.266 mmol) inTHF (5 mL) was added methyl 4-chloro-4-oxo-butyrate (0.011 g, 46 μL,1.05 mmol) at 0° C. The mixture was warmed to room temperature andstirred for 45 mins. The crude mixture was purified by HPLC to affordCompound 176 as an oil (TFA salt, 0.024 g, 52%). Exact mass calculatedfor C₂₈H₃₃ClN₆O₅ 568.22. found 569.5 (MH⁺). ¹H NMR (400 MHz,methanol-d₄) δ: 7.50 (s, 1H), 7.42-7.45 (m, 1H), 7.32-7.36 (m, 3H),7.15-7.18 (m, 2H), 7.05-7.07 (m, 1H), 6.28 (s, 1H), 4.29-4.30 (m, 2H),3.64 (s, 5H), 3.46-3.47 (m, 2H), 3.11-3.13 (m, 2H), 3.01-3.13 (m, 4H),2.58-2.59 (m, 2H), 2.53-2.55 (m, 2H), 1.26-1.28 (m, 5H).

Example 1.11 Preparation of1-(4-chloro-phenyl)-3-[4-[2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]urea(Compound 177). Method M

A suspension of5-{2-[4-[3-(4-chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (TFA salt, 0.042 g, 0.062 mmol) and 4M HCl indioxane (2 mL) was stirred at room temperature overnight. The mixturewas dried in vacuo to afford Compound 177 as an oil (HCl salt, 0.046 g,100%). Exact mass calculated for C₂₄H₂₇ClN₆O₂ 466.19. found 467.5 (MH⁺).

Example 1.12 Preparation of(4-{2-[4-[3-(4-chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperazin-1-yl)-aceticacid methyl ester (Compound 209). Method N

To a stirred solution of1-(4-chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperazin-1-yl-ethoxy)-phenyl]-urea(TFA salt, 0.063 g, 0.11 mmol) and DIEA (0.572 g, 77 μL, 0.44 mmol) inTHF (3 mL) was added methyl bromoacetate (0.019 g, 12 μL, 0.121 mmol) at0° C. The mixture was warmed to room temperature and stirred for 20 hrs.The crude mixture was purified by HPLC to afford Compound 209 as an oil(TFA salt, 0.053 g, 74%). Exact mass calculated for C₂₆H₃₁ClN₆O₄ 526.21.found 527.5 (MH⁺). ¹H NMR (400 MHz, acetonitrile-d₃) δ: 7.78-7.89 (m,2H), 7.77 (s, 1H), 7.54-7.77 (m, 1H), 7.43-7.48 (m, 3H), 7.25-7.29 (m,2H), 7.06-7.08 (m, 1H), 6.49 (s, 1H), 4.33-4.35 (t, J=4.55, 4.80 Hz,2H), 3.84 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.46-3.48 (t, J=4.55 Hz,2H), 3.39-3.41 (m, 8H).

Example 1.13 Preparation of1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea(Compound 17). Method O—Comprising Steps 1.13a to 1.13c to give a phenolStep 1.13a: Preparation of 6-amino-chromen-4-one

To a solution of 6-nitrochromone (2.0 g, 10.5 mmol) in methanol/ethylacetate (100 mL/20 mL) purged with argon, was added 5% Pd/C(Degussa-wet, 0.5 g) catalyst. Hydrogen gas was bubbled through theslurry with stirring until (2 hrs.) LCMS and TLC showed completeconversion of starting material to product. The spent palladium catalystwas filtered off through a celite, and the solid was washed withmethanol. The combined filtrate and washings were evaporated to produce6-amino-chromen-4-one (1.58 g, 94%) as a light yellow solid. LCMS m/z(%)=162 (M+H, 100), ¹H NMR (400 MHz, CDCl₃) δ: 7.79 (d, J=5.96 Hz, 1H),7.38 (d, J=2.86 Hz, 1H), 7.29 (d, J=8.88 Hz, 1H), 7.01 (dd, J=8.80 Hz,2.8 Hz, 1H), 6.26 (d, J=5.96 Hz, 1H), 5.29 (s, 2H).

Step 1.13b: Preparation of1-(4-chloro-phenyl)-3-(4-oxo-4H-chromen-6-yl)-urea

To a stirred and heated (80° C.) slurry of 6-aminochromone (3.0 g, 18.6mmol) in toluene (200 mL) was added 4-chlorophenyl isocyanate (3.2 g,20.5 mmol) and the mixture was refluxed further for 18 hours. Thereaction mixture was cooled and the precipitate was filtered and washedwith methanol. The residue was dried in vacuo to afford1-(4-chloro-phenyl)-3-(4-oxo-4H-chromen-6-yl)-urea (5.8 g, 99%) as ayellow powder. LCMS m/z (%)=315 (M+H³⁵Cl, 100), 317 (M+H³⁷Cl, 32.2) ¹HNMR (400 MHz, DMSO-d₆) δ: 9.09 (bs, 1H), 8.94 (bs, 1H), 8.29 (d, J=5.99Hz, 1H), 8.20 (d, J=2.69 Hz, 1H), 7.81 (dd, J=9.0, 2.75 Hz, 1H), 7.62(d, J=9.07 Hz, 1H), 7.52 (dd, J=6.84, 2.16 Hz, 2H), 7.35 (dd, J=6.85,2.11 Hz, 2H), 6.33 (d, J=5.98 Hz, 1H).

Step 1.13c: Preparation of1-(4-chloro-phenyl)-3-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea

To a stirred and ice-cooled solution of methyl hydrazine (1.46 g, 31.6mmol) in pyridine was added a slurry of1-(4-chloro-phenyl)-3-(4-oxo-4H-chromen-6-yl)-urea (2.5 g, 7.9 mmol) inpyridine over a period of 10 mins. The reaction mixture was stirredfurther at this temperature for 2 hours and then allowed to warm slowlyto ambient temperature. After 6 hrs the reaction mixture turned clear.The reaction was stirred at this temperature for 18 hours. Pyridine wasevaporated and the resulting dark colored residue was dissolved in DMSOand purified using a Varian Prep. HPLC system (20 mL/min., λ=240, 0.1%TFA/H₂O:0.1% TFA/CH₃CN). The two regio-isomers were separated. Thefractions containing the product were concentrated and dried in vacuo toproduce (1.78 g, 47%) as a colorless powder. LCMS m/z (%)=343 (M+H³⁵Cl,100), 345 (M+H³⁷Cl, 32.5). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.59 (bs, 1H),8.72 (bs, 1H), 8.48 (bs, 1H), 7.43 (dd, J=6.8, 2.07 Hz, 2H), 7.41 (d,J=1.83 Hz, 1H), 7.28 (dd, J=7.13, 2.09 Hz, 2H), 7.26 (d, J=2.72 Hz, 1H),6.89 (d, J=9.36 Hz, 1H), 6.21 (d, J=1.84 Hz, 1H), 3.67 (s, 3H).

Step 1.13d: Preparation of1-(4-chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea

To a stirred and ice-cooled solution of1-(4-chloro-phenyl)-3-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea(0.1 g, 0.2923 mmol), triphenyl phosphine (0.291 g, 1.1078 mmol) and1-(2-hydroxy ethyl)-pyrrolidine (0.127 g, 1.099 mmol) in THF (25 mL) wasadded diisopropyl azodicarboxylate (0.224 g, 1.104 mmol) slowly over 10minutes. The reaction mixture was allowed to warm to ambient temperatureand stirred further for 4 hrs at this temperature. THF was evaporatedand the syrup was dissolved in DMSO and purified using a Varianpreperative HPLC system (60 mL/min flow and λ=240 0.1% TFA/H₂O:0.1%TFA/CH₃CN). The fractions containing the product were evaporated. Thepink colored residue was subjected to 2^(nd) purification using SiO₂flash chromatography (eluant: 1% methanol in DCM to 15% methanol inDCM). The fractions containing the product were evaporated to give acolorless solid that was used directly in the next step.

Step 1.13e: Preparation of1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea

To a solution of1-(4-chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-ureain cold methanol was added a solution of N-chloro succinimide (0.044 g,0.3215 mmol) in methanol. The reaction mixture was stirred for 60minutes. Then the methanol was evaporated and the residue was purifiedusing silica flash chromatography with 15% methanol in DCM as eluant.The fractions containing the product were evaporated and dried in vacuoto afford1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea(Compound 17) (0.05 g, 38%) as an off-white solid. LCMS m/z (%)=474(M+H³⁵Cl³⁵Cl, 100), 476 (M+H³⁵Cl³⁷Cl, 81.7), 478 (M+H³⁷Cl³⁷Cl, 11.2). ¹HNMR (400 MHz, DMSO-d₆) δ: 8.83 (bs, 1H), 8.73 (bs, 1H), 7.61 (s, 1H),7.54 (dd, J=2.65, 2.69 Hz, 1H), 7.46 (dd, J=2.06, 2.11 Hz, 2H), 7.37 (d,J=2.7 Hz, 1H), 7.31 (dd, J=2.09, 2.04 Hz, 2H), 7.16 (d, J=9.03 Hz, 1H),4.2-4.0 (bm, 2H), 3.65 (s, 3H), 2.7-2.5 (bm, 2H), 2.4-2.3 (bm, 4H),1.7-1.5 (bm, 4H).

Example 1.14 Preparation of1-(2,4-difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(pyridin-2-ylmethoxy)-phenyl]-urea(Compound 28) Step 1.14a: Preparation of2-[2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxymethyl]-pyridine. MethodP

A mixture of 2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenol (100 mg, 0.46mmol), 2-bromomethylpyridine hydrobromide salt (140 mg, 0.55 mmol) andpotassium carbonate (158 mg, 1.15 mmol) in DMSO (4 mL) was stirred at100° C. overnight. The crude was purified by HPLC to provide the titlecompound as a brown solid (158 mg, 81%). Exact mass calculated forC₁₆H₁₄N₄O₃ 310.1. found 311.2 (MH⁺).

Step 1.14b: Preparation of3-(2-methyl-2H-pyrazol-3-yl)-4-(pyridin-2-ylmethoxy)-phenylamine MethodQ

To a solution of2-[2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy-methyl]-pyridine (158mg, 0.37 mmol) in THF (3 mL) and saturated ammonium chloride (1 mL) wasadded zinc dust (192 mg, 2.96 mmol) at 0° C. The mixture was stirred atthe same temperature for 15 minutes and then filtered through celite.The solution was concentrated in vacuo to give the title compound as asolid (150 mg, 100%). Exact mass calculated for C₁₆H₁₆N₄O 280.1. found281.4 (MH⁺).

Step 1.14c: Preparation of1-(2,4-difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(pyridin-2-ylmethoxy)-phenyl]-urea(Compound 28)

The title compound was prepared in a similar manner as described inMethod F to give an off-white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 3.68(s, 3H), 5.20 (s, 2H), 6.31 (d, J=2.02 Hz, 1H), 7.04-7.06 (m, 1H), 7.18(d, J=8.34 Hz, 1H), 7.27-7.34 (m, 2H), 7.37-7.47 (m, 4H), 7.87 (dt,J=2.02, 8.08 Hz, 1H), 8.00-8.07 (m, 1H), 8.48 (s, 1H), 8.59-8.60 (m,1H), 8.98-8.99 (m, 1H). Exact mass calculated for C₂₃H₁₉F₂N₅O₂ 435.2.found 436.4 (MH⁺).

Example 1.15 Preparation of2-(4-chloro-phenyl)-2-hydroxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-acetamide(Compound 95). Method R

A mixture of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine(100 mg, 0.35 mmol), 4-chloromandelic acid (98 mg, 0.525 mmol), HATU(200 mg, 0.525 mmol) and triethylamine (0.5 mL) in DMF (6 mL) was heatedat 50° C. overnight. The crude was purified by HPLC to provide the titlecompound as a semi-solid (24 mg, 15%). ¹H NMR (DMSO-d₆, 400 MHz) δ1.60-1.73 (m, 2H), 1.84-1.91 (m, 2H), 2.80-2.90 (m, 2H), 3.22-3.30 (m,4H), 3.65 (s, 3H), 4.25 (t, J=5.05 Hz, 2H), 6.26 (d, J=1.77 Hz, 1H),7.17 (d, J=9.09 Hz, 1H), 7.39-7.46 (m, 2H), 7.51-7.53 (m, 3H), 7.67 (d,J=2.53 Hz, 1H), 7.80 (dd, J=2.78, 8.84 Hz, 1H), 9.50 (s br, 1H), 10.0(s, 1H). Exact mass calculated for C₂₄H₂₇ClN₄O₃ 454.2. found 455.4(MH⁺).

Example 1.16 Preparation of 3-methyl-but-2-enoic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide(Compound 106) Method S

3-Methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-butyramide(20 mg, 0.054 mmol) was treated with NBS (10 mg, 0.054 mmol) in DMF (2mL) at room temperature for 2 hours. The crude was purified by HPLC toprovide the title compound as an off-white solid (6 mg, 25%). Exact masscalculated for C₂₁H₂₇BrN₄O₂ 446.1. found 447.2 (MH⁺).

Example 1.17 Preparation of4-bromo-5-[2-(2-bromo-ethoxy)-5-nitro-phenyl]-1-methyl-1H-pyrazole.Method T

A mixture of 5-[2-(2-bromo-ethoxy)-5-nitro-phenyl]-1-methyl-1H-pyrazole(200 mg, 0.61 mmole), and N-bromosuccinimide (0.61 mmole, 1.0 eq) in 2mL of DMF was stirred at 100° C. for 10 minutes in the Microwave. Themixture was quenched with water, extract with ethyl acetate, and driedin vacuo give the title compound as a yellow solid (200 mg, 81%). ¹H NMR(400 MHz, CDCl₃) δ 3.53-3.64 (m, 2H), 3.78 (s, 3H), 4.38-4.49 (m, 2H),7.11 (d, 1H), 7.57 (s, 1H), 8.23 (s, 1H), 8.39 (d, 1H). Exact masscalculated for C₁₂H₁₁Br₂N₃O₃ 402.9. found 406.1 (MH⁺).

Example 1.18 Preparation of pentanoic acid{3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-amide(Compound 179). Method U

A mixture of1-{2-[4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidin-4-ol(50 mg, 0.126 mmol), valeric anhydride (28 mg, 0.15 mmol) andtriethylamine (0.1 mL) in DMF (1 mL) was heated with microwaves at 80°C. for 10 minutes. The crude was purified by HPLC to provide the titlecompound as a yellow solid (27 mg, 45%). ¹H NMR (DMSO-d₆, 400 MHz) δ0.90 (t, J=7.33 Hz, 3H), 1.33 (guar, J=7.58 Hz, 2H), 1.47-1.51 (m, 1H),1.57 (quin, J=7.58 Hz, 2H), 1.68-1.90 (m, 2H), 2.30 (t, J=7.33 Hz, 2H),2.75-3.30 (m, 6H), 3.40-3.43 (m, 2H), 3.70-3.71 (m, 3H), 3.85-3.90 (m,1H), 4.22-4.50 (m, 2H), 7.22 (d, J=9.35 Hz, 1H), 7.53 (d, J=2.53 Hz,1H), 7.64 (d, J=8.84 Hz, 1H), 7.76 (dd, J=2.53, 9.09 Hz, 1H), 9.37 (s,br, 1H), 9.98 (s, 1H). Exact mass calculated for C₂₂H₃₁BrN₄O₃ 478.2.found 479.3 (MH⁺).

Example 1.19 Preparation of pentanoic acid[4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 203) Step 1.19a: Preparation of4-(2-chloro-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine. Method V

A mixture ofN-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide(450 mg, 1.33 mmol), concentrated HCl (0.9 mL) in THF (4 mL) was heatedwith microwave irradiation at 150° C. for 30 minutes. The crude wasconcentrated in vacuo to give the title compound as a brown oil. Exactmass calculated for C₁₂H₁₄ClN₂O 251.1. found 252.0 (MH⁺). This was usedwithout purification in next step.

Step 1.19b: Preparation of pentanoic acid[4-(2-chloro-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide

The title compound was prepared in a similar manner as described inMethod U to give a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 0.95 (t,J=7.33 Hz, 3H), 1.43 (guar, J=7.58 Hz, 2H), 1.72 (quin, J=7.60 Hz, 2H),2.40 (t, J=7.58 Hz, 2H), 3.72 (t, J=5.31 Hz, 2H), 4.04 (s, 3H), 4.25 (t,2H), 6.25 (d, 1H), 6.98-7.00 (m, 1H), 7.44 (s, br, 1H), 7.59-7.60 (m,1H), 7.64-7.66 (m, 1H), 7.81 (d, J=2.53 Hz, 1H). Exact mass calculatedfor C₁₇H₂₂ClN₃O₃ 335.1. found 336.3 (MH⁺).

Step 1.19c: Preparation of pentanoic acid[4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(Compound 203). Method W

A mixture of pentanoic acid[4-(2-chloro-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide (50 mg,0.15 mmol), 4-hydroxypiperidine (18 mg, 0.18 mmol), potassium carbonate(31 mg, 0.225 mmol) and catalytic amount of tetrabutyl ammonium iodidein DMF (1 mL) was heated with microwaves at 100° C. for 2.5 hours. Thecrude was purified by HPLC to provide the title compound as a stickysolid (51 mg, 85%). ¹H NMR (DMSO-d₆, 400 MHz) δ 0.89 (t, J=7.33 Hz, 3H),1.30 (guar, J=7.58 Hz, 2H), 1.40-1.48 (m, 1H), 1.54 (quin, J=7.58 Hz,2H), 1.66-1.82 (m, 2H), 2.28 (t, J=7.33 Hz, 2H), 2.82-2.89 (m, 1H),3.05-3.09 (m, 2H), 3.19-3.22 (m, 1H), 3.39-3.45 (m, 2H), 3.64 (d, J=2.53Hz, 3H), 3.85 (s, 1H), 4.11-4.18 (m, 4H), 6.25 (dd, J=2.02, 5.05 Hz,1H), 7.16 (d, J=9.09 Hz, 1H), 7.45 (dd, J=2.02, 5.31 Hz, 1H), 7.55 (d,J=2.78 Hz, 1H), 7.66 (dd, J=2.53, 9.09 Hz, 1H), 9.23 (s, br, 1H), 9.91(s, 1H). Exact mass calculated for C₂₂H₃₂N₄O₃ 400.2. found 401.3 (MH⁺).

Example 1.20 General Procedure of Chlorination. Preparation ofintermediate5-[2-(2-bromo-ethoxy)-5-nitro-phenyl]-4-chloro-1-methyl-1H-pyrazole.Method X

A mixture of 5-[2-(2-bromo-ethoxy)-5-nitro-phenyl]-1-methyl-1H-pyrazole(470 mg, 1.44 mmole), and N-chlorosuccinimide (1.44 mmole, 1.0 eq) in 2mL of DMF was stirred at 100° C. for 20 minutes in the Microwave. Themixture was quenched with water, extract with ethyl acetate, and driedin vacuo give the title compound as a yellow solid (462 mg, 89%). ¹H NMR(400 MHz, CDCl₃) δ 3.61 (t, 2H), 3.78 (s, 3H), 4.44 (t, 2H), 7.13 (d,1H), 7.57 (s, 1H), 8.23 (s, 1H), 8.40 (d, 1H). Exact mass calculated forC₁₂H₁₁ ⁸¹BrClN₃O₃ 359.0. found 362.0 (MH⁺).

Example 1.21 Preparation of1-[4-(2-azetidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-urea(Compound 87). Method Y

To a solution of 4-nitrophenyl chloroformate (51.5 mg, 0.255 mmol) in1,2-dichloroethane (4 mL) and pyridine (50 μL) was added5-amino-2,2-difluoro-1,3-benzodioxole (32 μL, 0.275 mmol). After 1 hour,4-(2-azetidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine(47.4 mg, 0.147 mmol) in 1,2-dichloroethane (5 mL) was added andstirring continued overnight. The resulting material was purified byHPLC. The product was dried in vacuo to afford Compound 87 as a whitesolid (40.7 mg, 50%). LCMS m/z (%)=472 (M+H, 100), ¹H NMR (400 MHz,DMSO-d₆) δ: 8.96 (bs, 1H), 8.73 (bs, 1H), 7.65 (d, J=2.10 Hz, 1H),7.47-7.41 (m, 2H), 7.36 (d, J=2.71 Hz, 1H), 7.30 (d, J=8.74 Hz, 1H),7.10-7.02 (m, 2H), 6.22 (d, J=1.84 Hz, 1H), 3.89 (t, J=5.51 Hz, 2H),3.67 (s, 3H), 2.98 (t, J=6.92 Hz, 4H), 2.60 (t, J=5.47 Hz, 2H), 1.86(quintet, J=6.90 Hz, 2H).

Example 1.22 Preparation of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-hydroxy-phenyl)-urea(Compound 25). Method Z

To a solution of triphosgene (19.7 mg, 0.066 mmol) in THF (4 mL) wasadded 4-(tert-butyl-dimethyl-silanyloxy)-phenylamine (48.4 mg, 0.217mmol). After 1 hour,3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine(62.3 mg, 0.171 mmol) in THF (5 mL) was added followed 30 min. later bytriethylamine (100 μL) and stirring continued overnight. The resultingmaterial was purified by HPLC. The isolated oil (80 mg) was dissolved inTHF (15 mL). To this solution, TBAF (0.165 mL of a 1.0 M in THFsolution, 0.165 mmol) was added. The reaction mixture was concentrated,yielding an oil which was purified by SiO₂ column chromatography(eluent: 20% methanol/80% dichloromethane) to afford Compound 25 as awhite solid (57.2 mg, 67%). LCMS m/z (%)=500 (M+H⁷⁹Br, 100), 502(M+H⁸¹Br, 89), ¹H NMR (400 MHz, DMSO-d₆) δ: 9.03 (s, 1H), 8.59 (bs, 1H),8.35 (bs, 1H), 7.59 (s, 1H), 7.51 (dd, J=8.97, 2.71 Hz, 1H), 7.33 (d,J=2.70 Hz, 1H), 7.20 (d, J=8.86 Hz, 1H), 7.12 (d, J=9.04 Hz, 1H), 6.67(d, J=8.85 Hz, 1H), 4.13-4.04 (m, 1H), 4.04-3.95 (m, 1H), 3.66 (s, 3H),2.77-2.66 (m, 1H), 2.66-2.57 (m, 1H), 2.41-2.30 (m, 4H), 1.65-1.55 (m,4H).

Example 1.23 Preparation of2-(tert-butyl-diphenyl-silanyloxy)-4-chloro-phenylamine. Method AA

2-Amino-5-chlorophenol (0.949 g, 6.61 mmol),tert-butylchlorodiphenylsilane (2.50 mL, 9.61 mmol), and imidazole(1.335 g, 19.6 mmol) were dissolved in THF (50 mL). Several days later,the reaction mixture was concentrated to give an oil which was purifiedby SiO₂ column chromatography (eluent: 45% dichloromethane/55% hexanes).The product was dried in vacuo to afford2-(tert-butyl-diphenyl-silanyloxy)-4-chloro-phenylamine as a yellow oil(784.2 mg, 31%). ¹H NMR (400 MHz, DMSO-d₆) δ: 7.72-7.64 (m, 4H),7.55-7.43 (m, 6H), 6.71 (d, J=8.45 Hz, 1H), 6.65 (dd, J=8.46, 2.27 Hz,1H), 6.10 (d, J=2.26 Hz, 1H), 1.05 (s, 9H).

Example 1.24 Preparation of the intermediate5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole. Method AB

A solution of N-methylpyrazole (5.12 g, 62.4 mmol) in THF (100 mL) wascooled to −78° C. and 2.5M n-butyllithium in hexane (27.5 mL, 68.8 mmol)was added. After stirring for 30 minutes at the same temperature, 0.5 Mzinc chloride in THF (107 mL, 53.5 mmol) and 1 M zinc chloride indiethyl ether (15.3 mL, 15.2 mmol) were added. The mixture was allowedto warm to room temperature and 2-iodo-4-nitroanisole (17.4 g, 62.4mmol) followed by tetrakis(triphenylphosphine)palladium (3.6 g, 3.1mmol) were added. After stirring at 60° C. for 20 hours, the blacksolution was concentrated on a rotary evaporator, and extracted withethyl acetate and brine. Combined organic layers were dried overmagnesium sulfate, filtered, and partly concentrated until a solidstarted to precipitate. Hexane was added, precipitate was filtered off,and washed with a cold 3: 1 mixture of hexane/ethyl acetate to give5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (8.6 g, 36.9 mmol,59%) as a tan solid. LCMS m/z (%)=234 (M+H, 100). ¹H NMR (400 MHz,CDCl₃) δ: 8.34 (dd, J=2.8, 9.2 Hz, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.56 (d,J=2.0 Hz, 1H), 7.08 (d, J=9.2 Hz, 1H), 6.31 (d, J=1.6 Hz, 1H), 3.96 (s,3H), 3.74 (s, 3H).

Example 1.25 Preparation of the intermediate4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine. Method AC

To a solution of 5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (7.95g, 34.1 mmol) in acetic acid (250 mL) was added zinc dust (11.7 g, 179mmol) in portions under cooling in an ice bath over a period of 10minutes. After stirring for 30 min at room temperature, solids werefiltered of through celite. Filtrate was concentrated and residue waspurified by SiO₂ column chromatography (Eluent: methylenechloride/methanol 20: 1) to give4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (4.34 g, 21.4 mmol,62%) as an oil. LCMS m/z (%)=204 (M+H). ¹H NMR (400 MHz, CDCl₃) δ: 7.51(d, J=1.8 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.76 (dd, J=2.8, 8.7 Hz, 1H),6.62 (d, J=2.8 Hz, 1H), 6.22 (d, J=1.8 Hz, 1H), 3.74 (s, 3H), 3.73 (s,3H), 3.24-3.55 (broad s, 2H).

Example 1.26 Preparation of the intermediate1-[3-(2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea.Method AD

To a mixture of1-[3-(2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-chloro-phenyl)-urea(6.35 g, 17.8 mmol) and dichloroethane (500 mL), tribromoborane (10 mL,106 mmol) was added. The mixture was allowed to warm to roomtemperature. After stirring over the weekend, the mixture was cooled inan ice bath and a mixture of ice cold ammonium hydroxide and water (ca.100 mL) was added slowly. The mixture was transferred into a separatoryfunnel and extracted with methylene chloride and water. Solid in thewater phase was filtered off and washed with water to give1-[3-(2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-ureaas a white solid (4.92 g, 90% pure, 12.7 mmol, 71%). Combined organicphases were dried over MgSO₄, filtered, and concentrated to affordadditional1-[3-(2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-ureaas a white solid (1.71 g, 4.99 mmol, 28%). Overall yield: 99%. LCMS m/z(%)=343.1 (M+H). ¹H NMR (400 MHz, CDCl₃) δ: 9.60 (br s, 1H), 8.78 (s,1H), 8.53 (s, 1H), 7.48-7.42 (m, 3H), 7.32-7.27 (m, 4H), 6.91-6.89 (m,1H), 6.21 (d, J=1.8 Hz, 1H), 3.68 (s, 3H).

Example 1.27 Preparation of1-[3-(2-methyl-2H-pyrazol-3-yl)-4-(morpholin-2-ylmethoxy)-phenyl]-3-phenyl-urea(Compound 174). Method AE

To a solution of2-[4-[3-(4-chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxymethyl]-morpholine-4-carboxylicacid benzyl ester (30 mg, 0.052 mmol) in methanol (5 mL), was added Pdon carbon (10%, 50% H₂O, 50 mg, 0.024 mmol), and the mixture was stirredunder a hydrogen atmosphere (balloon) at room temperature for 2 hours.Solids were filtered off through celite and mixture was purified by HPLCto give Compound 174 as a white solid (TFA salt, 9.8 mg, 0.0176 mmol,36%). LCMS m/z (%)=408.5 (M+H). ¹H NMR (400 MHz, MeOH-d₄) δ: 7.43-7.38(m, 2H), 7.32-7.30 (m, 3H), 7.20-7.16 (m, 2H), 7.00 (d, J=8.9 Hz, 1H),6.99-6.90 (m, 1H), 6.23 (s, 1H), 4.01-3.98 (m, 3H), 3.88-3.85 (m, 1H),3.72-3.69 (m, 1H), 3.65 (s, 3H), 3.14-3.09 (m, 2H), 2.98-2.92 (m, 1H),2.79-2.73 (m, 1H).

Example 1.28 Amination with a boronic acid and copper(II) acetate,preparation of[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-(4-chloro-phenyl)-amine(Compound 305). Method AF

A mixture of3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine(0.050 g, 0.15 mmol), 4-chlorophenyl boronic acid (0.035 g, 0.23 mmol),copper(II) acetate (0.0273 g, 0.15 mmol) and triethylamine (0.042 mL,0.3 mmol) in methylene chloride (3 mL) was stirred at room temperaturefor 48 hours. The reaction mixture was concentrated to give a crudeproduct that was subjected to a purification by prep HPLC. Thecorresponding fractions were collected and lyophilized to give aTFA-salt of Compound 305 as a gray solid in 21.3% yield. LCMS: Exactmass calculated for C₂₂H₂₄Cl₂N₄O₂ is 446.13. found m/z=447.1 (M+H).

Example 1.29 Reductive amination, preparation of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-3-(4-chloro-phenyl)-urea(Compound 335). Method AG

A mixture of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)-phenyl]-3-(4-chloro-phenyl)-urea(0.030 g, 0.06 mmol) and formaldehyde (37% aqueous solution, 0.015 mL,0.18 mmol) in 1,2-dichloroethane (2 mL) was treated with sodiumtriacetoxyborohydride (0.025 g, 0.12 mmol). The mixture was stirred atroom temperature under argon atmosphere overnight, diluted with ethylacetate and washed with saturated sodium bicarbonate. The organic layerwas separated, dried over anhydrous sodium sulfate, filtered andconcentrated to give a crude product that was subjected to apurification by prep HPLC. The corresponding fractions were collectedand lyophilized to give a TFA-salt of Compound 335 as a white solid in54.7% yield. LCMS: Exact mass calculated for C₂₄H₂₇BrClN₅O₂ is 531.10.found m/z=532.2 (M+H).

Example 1.30 Preparation ofN-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methanesulfonylamino-piperidin-1-yl)-ethoxy]phenyl]-3-trifluoromethyl-benzamide(Compound 757). Method AH

N-[4-[2-(4-Amino-piperidin-1-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(0.038 g, 0.073 mmol) was dissolved in DMA (2.0 mL) in a vial with stirbar. Methanesulfonyl chloride (0.0085 g, 0.11 mmol) was added and thereaction was stirred at rt overnight. The reaction was concentrated,added to NaHCO₃ (5 mL), and the solution was extracted with EtOAc (2×20mL). The organic extracts were dried (Na₂SO₄), filtered, concd andpurified by prep HPLC to afford the title compound (0.016 g, 0.026 mmol,35%, TFA salt) as a white solid. LCMS m/z (%)=600 (M+H³⁵Cl, 100), 602(M+H³⁷Cl, 36). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.54 (s, 1H), 9.30 (s, 1H),8.30 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.97 (m, 2H), 7.80 (m, 1H), 7.72(d, J=2.6 Hz, 1H), 7.68 (s, 1H), 7.31 (m, 1H), 4.40 (m, 1H), 4.32 (m,1H), 3.69 (s, 3H), 3.50-2.90 (m, 7H), 2.95 (s, 3H), 2.00-1.50 (m, 4H).

Example 1.31 Preparation of1-(4-Chloro-phenyl)-3-[4-[2-((R)-1-methyl-piperidin-2-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea(Compound 353) Method AI

2-{2-[4-[3-(4-Chloro-phenyl)-ureido]-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (240 mg, 0.434 mmole) was added into solution of1M LiAlH₄ in THF (3.472 mL, 3.472 mmole) and THF (10 mL) at 0° C.Reaction mixture was heated to reflux at 75° C. for 8 hours. The crudereaction mixture was quenched with water at 0° C. while stirring andNa₂SO₄ was added into crude, and then stirred at room temperature foranother 30 minutes. The resulting solid was filtered, washed with ethylacetate and supernatant was concentrated and dried in vacuo. Crude waspurified through HPLC gave the title compound as a pale pink solid as aTFA salt. Exact mass calculated for C₂₅ClH₃₀N₅O₂ 467.2. found 468.5(MH⁺).

Example 1.32 Preparation ofN-{3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenyl}-3-fluoro-benzamide(Compound 637)

To a solution of3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(4-methoxypiperidin-1-yl)ethoxy)benzenamine(0.024 g, 0.060 mmol) in CH₂Cl₂ (0.9 mL) was added 3-fluorobenzoylchloride (0.0086 mL, 0.0714 mmol) and triethylamine (0.011 mL, 0.077mmol). The reaction was stirred for 1 h, and concentrated and purifiedby RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.027 g,56%). LCMS m/z (%)=531 (M+H⁷⁹Br, 94), 533 (M+H⁸¹Br, 100). ¹H NMR (400MHz, DMSO-d₆) δ: 10.42 (s, 1H), 7.95 (dd, J=2.1, 8.5 Hz, 1H), 7.82 (d,J=7.9 Hz, 1H), 7.79-7.75 (m, 1H), 7.74-7.72 (m, 1H), 7.68 (d, J=8.6 Hz,1H), 7.63-7.57 (m, 1H), 7.45 (dt, J=2.6, 8.3 Hz, 1H), 7.29 (dd, J=3.7,9.1 Hz, 1H), 4.47-4.38 (m, 1H), 4.35-4.28 (m, 1H), 3.69 (s, 3H), 3.27(s, 3H), 3.53-1.37 (m, 11H).

Example 1.33 Preparation ofN-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-fluoro-4-methyl-benzamide(Compound 559)

To a solution of3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine(0.040 g, 0.12 mmol) in CH₂Cl₂ (1.8 mL) was added3-fluoro-4-methylbenzoyl chloride (0.025 mL, 0.14 mmol) andtriethylamine (0.022 mL, 0.15 mmol). The reaction was stirred for 1 h,and concentrated and purified by RP-HPLC. Lyophilization afforded a TFAsalt as a brown oil (0.0096 g, 14%). LCMS m/z (%)=473 (M+H³⁵Cl, 100),475 (M+H³⁷Cl, 27). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.31 (s, 1H), 7.96 (dd,J=2.6, 11.6 Hz, 1H), 7.76-7.72 (m, 3H), 7.67 (s, 1H), 7.49-7.44 (m, 1H),7.30 (d, J=9.1 Hz, 1H), 4.48-4.44 (m, 1H), 4.38-4.30 (m, 1H), 3.66 (s,3H), 4.00-2.90 (m, 10H), 2.32 (s, 3H).

Example 1.34 Preparation of1-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)-3-(3-chlorophenyl)urea(Compound 231)

A solution of3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine(0.040 g, 0.12 mmol) in CH₂Cl₂ (1 mL) was treated with 3-chlorophenylisocyanate (0.015 mL, 0.125 mmol). The reaction was stirred overnight,and concentrated and purified by RP-HPLC. Lyophilization afforded a TFAsalt as a brown solid (0.016 g, 27%). LCMS m/z (%)=490 (M+H³⁵Cl³⁵Cl,100), 492 (M+H³⁵Cl³⁷Cl, 76), 494 (M+H³⁷Cl³⁷Cl, 15). ¹H NMR (400 MHz,DMSO-d₆) δ: 8.92 (s, 1H), 8.79 (s, 1H), 7.74 (t, J=2.0 Hz, 1H),7.70-7.63 (m, 1H), 7.57 (dd, J=2.7, 6.3 Hz, 1H), 7.41 (d, J=2.7 Hz, 1H),7.36-7.28 (m, 2H), 7.21 (d, J=9.0 Hz, 1H), 7.04 (dt, J=1.9, 7.4 Hz, 1H),4.22-4.15 (m, 1H), 4.11-4.05 (m, 1H), 3.70 (s, 3H), 3.56-3.51 (m, 4H),2.66-2.48 (m, 2H), 2.42-2.30 (m, 4H).

Example 1.35 Preparation of1-(4-chloro-benzyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-urea(Compound 666)

A solution of3-(1-methyl-1H-pyrazol-5-yl)-4-(3-morpholinopropoxy)benzenamine (0.025g, 0.079 mmol) in CH₂Cl₂ (0.6 mL) was treated with 4-chlorobenzylisocyanate (0.012 mL, 0.083 mmol). The reaction was stirred for 1 h, andconcentrated and purified by RP-HPLC. Lyophilization afforded a TFA saltas a white solid (0.037 g, 78%). LCMS m/z (%)=484 (M+H³⁵Cl, 100), 486(M+H³⁷Cl, 38). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.60 (s, 1H), 8.63 (s, 1H),7.46 (d, J=1.8 Hz, 1H), 7.43 (dd, J=2.6, 8.9 Hz, 1H), 7.40-7.29 (m, 4H),7.07 (d, J=9.0 Hz, 1H), 6.75-6.70 (m, 1H), 6.25 (d, J=1.8 Hz, 1H), 4.26(d, J=5.8 Hz, 2H), 4.02-3.90 (m, 4H), 3.65 (s, 3H), 3.58 (t, J=12.0 Hz,2H), 3.34 (d, J=12.4 Hz, 2H), 3.09-2.92 (m, 4H), 2.06-1.97 (m, 2H).

Example 1.36 Preparation of3-chloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide(Compound 512)

To a solution of3-(1-methyl-1H-pyrazol-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine(0.029 g, 0.10 mmol) in CH₂Cl₂ (1.5 mL) was added 3-chlorobenzoylchloride (0.015 mL, 0.12 mmol) and triethylamine (0.018 mL, 0.13 mmol).The reaction was stirred for 1 h, and concentrated and purified byRP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.037 g,87%). LCMS m/z (%)=425 (M+H³⁵Cl, 100), 427 (M+H³⁷Cl, 42). ¹H NMR (400MHz, DMSO-d₆) δ: 10.40 (s, 1H), 8.01-8.00 (m, 1H), 7.94-7.87 (m, 2H),7.72 (d, J=2.6 Hz, 1H), 7.70-7.67 (m, 1H), 7.60-7.55 (m, 1H), 7.49 (d,J=1.8 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.31 (d, J=1.8 Hz, 1H), 4.32-4.28(m, 2H), 3.69 (s, 3H), 3.58-3.52 (m, 2H), 3.35-3.25 (m, 2H), 2.95-2.82(m, 2H), 1.95-1.85 (m, 2H), 1.78-1.68 (m, 2H).

Example 1.37 Preparation of3-fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide(Compound 487)

To a solution of3-(1-methyl-1H-pyrazol-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine(0.029 g, 0.10 mmol) in CH₂Cl₂ (1.5 mL) was added3-fluoro-4-(trifluoromethyl)benzoyl chloride (0.018 mL, 0.12 mmol) andtriethylamine (0.018 mL, 0.13 mmol). The reaction was stirred for 1 h,and concentrated and purified by RP-HPLC. Lyophilization afforded a TFAsalt as a brown oil (0.042 g, 88%). LCMS m/z (%)=477 (M+H, 100). ¹H NMR(400 MHz, DMSO-d₆) δ: 10.55 (s, 1H), 8.07-7.95 (m, 3H), 7.88 (dd, J=2.6,9.0 Hz, 1H), 7.73 (d, J=2.6 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.27 (d,J=9.0 Hz, 1H), 6.31 (d, J=1.8 Hz, 1H), 4.33-4.29 (m, 2H), 3.69 (s, 3H),3.58-3.52 (m, 2H), 3.35-3.25 (m, 2H), 2.92-2.81 (m, 2H), 1.95-1.85 (m,2H), 1.80-1.69 (m, 2H).

Example 1.38 Preparation of1-{3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea(Compound 298)

4-Chlorophenylisocyanate (19.0 mg, 0.124 mmol) was added to a solutionof1-{2-[4-amino-2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-azetidin-3-ol(40.0 mg, 0.124 mmol) in dichloromethane (2.0 mL) and DMF (0.1 mL), andthe mixture stirred at room temperature overnight. The solution wasconcentrated and purified by RP-HPLC. The collected fractions wereconcentrated and 12% sodium hydroxide (aq) (0.2 mL) was added to give pH9. The solution was extracted into ethyl acetate and the organic layerwas dried over sodium sulfate, filtered, and evaporated to dryness togive a white solid (28 mg, 47%). LCMS m/z (%)=476 (M+H³⁵Cl, 100), 478(M+H³⁷Cl, 67). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.81 (bs, 1H), 8.71 (bs,1H), 7.60 (s, 1H), 7.53-7.50 (m, 1H), 7.47 (d, J=2.08 Hz, 1H), 7.46 (d,J=2.10 Hz, 1H), 7.36 (d, J=2.71 Hz, 1H), 7.32 (d, J=2.11 Hz, 1H), 7.30(d, J=2.04 Hz, 1H), 7.11 (d, J=9.06 Hz, 1H), 5.19 (d, J=8.00 Hz, 1H),4.10-4.00 (m, 1H), 3.99-3.85 (m, 2H), 3.65 (s, 3H), 3.40-3.30 (m, 2H),2.70-2.55 (m, 4H).

Example 1.39 Preparation of1-[4-[2-(7-aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(3-trifluoromethyl-benzyl)-urea(Compound 710)

4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine(50.0 mg, 0.13 mmol) was added to a solution of4-nitrophenylchloroformate (26.0 mg, 0.13 mmol) in 1,2-dichloroethane(4.0 mL) and the mixture stirred at room temperature for 1 hour. To theresulting precipitate mixture was added 3-trifluoromethylbenzylamine(0.022 mL, 0.15 mmol) and N,N-diisopropylethylamine (0.030 mL, 0.17mmol), and the mixture stirred an additional 1 hour. The mixture wasconcentrated and purified by RP-HPLC. The collected fractions wereconcentrated and 12% sodium hydroxide (aq) (0.2 mL) was added to give pH9. The solution was extracted into ethyl acetate and the organic layerwas dried over sodium sulfate, filtered, and evaporated to dryness togive a white solid (49 mg, 65%). LCMS m/z (%)=592 (M+H⁷⁹Br, 100), 594(M+H⁸¹Br, 67). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.67 (bs, 1H), 7.67 (bs,1H), 7.65-7.59 (m, 4H), 7.53-7.50 (m, 1H), 7.33 (d, J=2.69 Hz, 1H), 7.12(d, J=9.04 Hz, 1H), 6.77-6.74 (m, 1H), 4.40 (d, J=4.0 Hz, 2H), 4.08-3.98(m, 2H), 3.67 (s, 3H), 3.12 (m, 2H), 2.59-2.55 (m, 2H), 1.56-1.54 (m,4H), 1.17-1.15 (m, 4H).

Example 1.40 Preparation of1-[4-[2-(7-aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,4-difluoro-benzyl)-urea(Compound 734)

4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine(50.0 mg, 0.13 mmol) was added to a solution of4-nitrophenylchloroformate (26.0 mg, 0.13 mmol) in 1,2-dichloroethane(4.0 mL) and the mixture stirred at room temperature for 1 hour. To theresulting precipitate mixture was added 2,4-difluorobenzylamine (0.030mL, 0.25 mmol) and N,N-diisopropylethylamine (0.030 mL, 0.17 mmol), andthe mixture stirred an additional 1 hour. The mixture was concentratedand purified by RP-HPLC. The collected fractions were concentrated and12% sodium hydroxide (aq) (0.2 mL) was added to give pH 9. The solutionwas extracted into ethyl acetate and the organic layer was dried oversodium sulfate, filtered, and evaporated to dryness to give a whitesolid (62 mg, 87%). LCMS m/z (%)=560 (M+H⁷⁹Br, 100), 562 (M+H⁸¹Br, 91).¹H NMR (400 MHz, DMSO-d₆) δ: 8.59 (bs, 1H), 7.58 (bs, 1H), 7.48-7.38 (m,2H), 7.29 (bs, 1H), 7.24-7.18 (m, 1H), 7.10-7.04 (m, 2H), 6.60-5.59 (m,1H), 4.29 (d, J=4.0 Hz, 2H), 4.06-3.96 (m, 2H), 3.64 (s, 3H), 3.11 (bs,2H), 2.58-2.54 (m, 2H), 1.54-1.52 (m, 4H), 1.15-1.13 (m, 4H).

Example 1.41 Preparation of4-fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide(Compound 281) Step 1.41a: General Procedure of Mitsunobu. Preparationof 4-{2-[2-(2-Methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-morpholine

A mixture of triphenylphosphine (7.5 g, 1.8 eq), anddiisopropylazodicarboxylate (5.66 mL, 1.8 eq) in 50 mL THF was stirredat 0° C. for 10 minutes, then2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenol (3.5 g, 15.9 mmole), and2-morpholin-4-yl-ethanol (3.66 mL, 1.8 eq) was added into the mixture at0° C. Reaction mixture was stirred at room temp for another 1 hour. Themixture was purified by HPLC to give title compound as a yellow gummysolid (9.436 g, 89%). Exact mass calculated for C₁₆H₂₀N₄O₅ 332.2. found333.3 (MH⁺).

Step 1.41b: Preparation of3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine

To a solution of4-{2-[2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-morpholine(1.913 g, 2.88 mmole), in saturated ammonium chloride solution (6 mL),water (6 mL) and THF (12 mL) was added zinc dust (1.123 g, 6 eq) at 0°C. The mixture was stirred at room temp for 1 hour and then filtered offthrough celite. The solution was dried in vacuo to give title compoundas a yellow gummy solid (1.87 g, 99%). Exact mass calculated forC₁₆H₂₂N₄O₂302.2. found 303.4 (MH⁺).

Step 1.41c: Preparation of2,4-Difluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide.(Compound 281)

A mixture of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine(200 mg, 0.66 mmole), 2,4-difluoro-benzoyl chloride (140 mg, 1.2 eq),and triethylamine (0.2 mL, 2 eq) in 3 mL THF was stirred at roomtemperature for 10 minutes. The mixture was purified by HPLC to givetitle compound as a white solid (99 mg, 34%). ¹H NMR (Acetone-d₆, 400MHz) δ 2.92-3.06 (m, 2H), 3.13-3.17 (m, 2H), 3.50-3.58 (m, 4H), 3.68 (s,3H), 3.82-3.85 (m, 2H), 4.36 (t, 2H), 6.29 (s, 1H), 7.24 (d, J=9.09 Hz,2H), 7.44 (dt, J=10.1, 2.78 Hz, 1H), 7.49 (s, 1H), 7.67 (s, 1H),7.72-7.79 (m, 1H), 7.81 (dd, J=9.09, 2.78 Hz, 1H). Exact mass calculatedfor C₂₃H₂₄F₂N₄O₃ 442.2. found 443.5 (MH⁺).

Example 1.42 Preparation ofN-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide(Compound 282)

A solution of HATU (98.0 mg, 0.260 mmol), triethylamine (55.7 μl, 0.400mmol) and 4-trifluoromethyl-benzoic acid (49.0 mg, 0.260 mmol) in THF(1.0 mL) was stirred at room temperature. After 15 min,3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine(60.0 mg, 0.200 mmol) was added, and the mixture was stirred at 100° C.for 10 minutes in microwave. The mixture was purified by HPLC to givetitle compound as a white solid (TFA salt, 27 mg, 28%). ¹H NMR (DMSO-d₆,400 MHz) δ 2.96-3.10 (m, 2H), 3.16-3.19 (m, 2H), 3.52-3.60 (m, 4H), 3.70(s, 3H), 3.84-3.87 (m, 2H), 4.39 (t, J=5.05 Hz, 2H), 6.31 (d, J=1.77 Hz,1H), 7.28 (d, J=9.09 Hz, 1H), 7.51 (d, J=1.77 Hz, 1H), 7.75 (d, J=2.78Hz, 1H), 7.94 (d, J=8.34 Hz, 2H), 8.16 (d, J=8.84 Hz, 2H), 8.89 (s, 1H),10.5 (s, 1H). Exact mass calculated for C₂₄H₂₅F₃N₄O₃ 474.2. found 475.4(MH⁺).

Example 1.43 Preparation ofN-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide(Compound 435)

A solution of HATU (113 mg, 0.30 mmol), triethylamine (55.7 μl, 0.400mmol) and 3-trifluoromethyl-benzoic acid (57 mg, 0.30 mmol) in DMF (1.0mL) was stirred at room temperature. After 15 min,3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine(57.0 mg, 0.200 mmol) was added, and the mixture was stirred at 100° C.for 10 minutes in microwave. The mixture was purified by HPLC to givetitle compound as a burgundy oil (TFA salt, 42 mg, 46% yield). Exactmass calculated for C₂₄H₂₅F₃N₄O₂ 458.2. found 459.4 (MH⁺).

Example 1.44 Preparation ofN-[4-[2-(3,3-difluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-3-methyl-benzamide(Compound 546)

A mixture of4-[2-(3,3-Difluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine(64 mg, 0.20 mmole), 4-fluoro-3-methyl-benzoyl chloride (52 mg, 0.30mmole), and triethylamine (56.5 μL, 0.40 mmole) in 1 mL THF was stirredat room temperature for 10 minutes. The mixture was purified by HPLC togive the title compound as a white solid (TFA salt, 29 mg, 32% yield).Exact mass calculated for C₂₄H₂₅F₃N₄O₂ 458.2. found 459.3 (MH⁺).

Example 1.45 Preparation of4-fluoro-3-methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-((S)-1-methyl-pyrrolidin-2-ylmethoxy)-phenyl]-benzamide(Compound 547)

A mixture of3-(2-Methyl-2H-pyrazol-3-yl)-4-(1-methyl-pyrrolidin-2-ylmethoxy)-phenylamine(64 mg, 0.23 mmole), 4-fluoro-3-methyl-benzoyl chloride (60 mg, 0.35mmole), and triethylamine (63.4 μL, 0.46 mmole) in 1 mL THF was stirredat room temperature for 10 minutes. The mixture was purified by HPLC togive the title compound as a white solid (TFA salt, 92 mg, 95% yield).Exact mass calculated for C₂₄H₂₇FN₄O₂ 422.2. found 423.2 (MH⁺).

Example 1.46 Preparation ofN-{3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenyl}-3,4-difluoro-benzamide(Compound 579)

A mixture of3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenylamine(95 mg, 0.25 mmole), 3,4-difluoro-benzoyl chloride (40 μL, 0.301 mmole),and triethylamine (70.2 μL, 0.501 mmole) in 1 mL THF was stirred at roomtemperature for 10 minutes. The mixture was purified by HPLC to give thetitle compound as a white solid (TFA salt, 60 mg, 46% yield). ¹H NMR(DMSO-d₆, 400 MHz) δ 1.22 (dd, J=19.71, 6.57 Hz, 3H), 1.45-1.53 (m, 1H),1.72-1.89 (m, 2H), 2.07-2.14 (m, 1H), 2.79-2.98 (m, 1H), 3.08-3.15 (m,1H), 3.31-3.44 (m, 2H), 3.59-3.65 (m, 1H), 3.68 (d, J=4.80 Hz, 3H),4.21-4.46 (m, 2H), 7.29 (dd, J=9.85 Hz, 6.82 Hz, 1H), 7.60-7.67 (m, 1H),7.66 (s, 1H), 7.70-7.72 (m, 1H), 7.84-7.88 (m, 1H), 7.94 (dt, J=9.09,2.78, 2.53 Hz, 1H), 8.01-8.06 (m, 1H), 9.22-9.48 (m, 1H from TFA), 10.4(s, NH). Exact mass calculated for C₂₄H₂₅ ⁷⁹BrF₂N₄O₂, 518.1. found519.3, 521.5 (MH⁺).

Example 1.47 Preparation ofN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-((R)-1-methyl-pyrrolidin-3-yloxy)-phenyl]-3,4-difluoro-benzamide(Compound 585)

A mixture of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-((R)-1-methyl-pyrrolidin-3-yloxy)-phenylamine(88 mg, 0.25 mmole), 3,4-difluoro-benzoyl chloride (40 μL, 0.30 mmole),and triethylamine (70 μL, 0.5 mmole) in 1 mL THF was stirred at roomtemperature for 10 minutes. The mixture was purified by HPLC to give thetitle compound as a white solid (TFA salt, 24 mg, 19% yield). ¹H NMR(CD₃OD, 400 MHz) δ 2.17-2.31 (m, 1H), 2.71-2.84 (m, 2H), 2.87-2.97 (m,2H), 3.14-3.25 (m, 1H), 3.38-3.48 (m, 1H), 3.72-3.79 (m, 1H), 3.75 (s,3H), 3.89-3.97 (m, 1H), 5.17-5.24 (m, 1H), 7.17-7.30 (m, 1H), 7.41-7.47(m, 1H), 7.56-7.62 (m, 1H), 7.63-7.69 (m, 1H), 7.78-89 (m, 1H),7.88-7.93 (m, 2H). Exact mass calculated for C₂₂BrH₂₁F₂N₄O₂ 490.1. found491.5, 493.5 (MH⁺).

Example 1.48 Preparation ofN-[4-[2-((S)-3-hydroxy-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide(Compound 586)

A solution of HATU (183 mg, 0.482 mmol), triethylamine (100 μl, 0.741mmol) and 4-trifluoromethyl benzoic acid (92 mg, 0.482 mmol) in THF (1.0mL) was stirred at room temperature. After 15 min,(S)-1-{2-[4-Amino-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-pyrrolidin-3-ol(112 mg, 0.370 mmol) was added, and the mixture was stirred at 100° C.for 10 minutes in microwave. The mixture was purified by HPLC to givethe title compound as a white solid (TFA salt, 58 mg, 33% yield). ¹H NMR(DMSO-d₆, 400 MHz) δ 1.67-1.74 (m, 1H), 1.78-1.90 (m, 1H), 2.09-2.18 (m,1H), 2.88-2.97 (m, 1H), 3.31-3.37 (m, 1H), 3.47-3.61 (m, 2H), 3.69 (s,3H), 4.31-4.36 (m, 4H), 6.31 (s, 1H), 7.24-7.28 (m, 1H), 7.50 (s, 1H),7.75 (s, 1H), 7.90 (d, J=8.84 Hz, 1H), 7.94 (d, J=8.34 Hz, 2H), 8.16 (d,J=8.34 Hz, 2H), 9.93-10.11 (m, 1H), 10.5 (s, 1H). Exact mass calculatedfor C₂₄H₂₅F₃N₄O₃ 474.2. found 475.3 (MH⁺).

Example 1.49 Preparation of3-fluoro-N-[4-[2-(4-formyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 752)

A mixture ofN-[4-(2-Bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide(83 mg, 0.198 mmole), and piperazine-1-carbaldehyde (27 mg, 0.238mmole), and K₂CO₃ (110 mg, 0.794 mmole) in 2 mL DMF was stirred at 120°C. for 20 minutes in microwave. The mixture was purified by HPLC to givetitle compound as a white solid as a TFA salt. Exact mass calculated forC₂₄FH₂₆N₅O₃ 451.2. found 452.2 (MH⁺), ¹HNMR (CD₃CN, 400 MHz) δ 3.15-3.32(m, 4H), 3.66-3.71 (m, 4H), 3.71-3.76 (m, 2H), 3.74 (s, 3H), 4.60 (t,J=4.80 Hz, 2H), 6.30 (d, J=1.77 Hz, 1H), 7.23 (d, J=8.84 Hz, 1H), 7.37(dd, J=8.59, 2.78 Hz, 1H), 7.50 (d, J=1.77 Hz, 1H), 7.54-7.61 (m, 1H),7.73-7.77 (m, 1H), 7.81 (d, J=2.53 Hz, 1H), 7.85 (d, J=7.83 Hz, 1H),7.94 (dd, J=9.09, 2.53 Hz, 1H), 8.08 (s, 1H), 9.68 (s, NH).

Example 1.50 Preparation ofN-[4-[2-(4-acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 755) Step 1.50a: Preparation of4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine

To a solution ofN-[4-(2-Bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (3g, 8.9 mmole) in methanol (6 mL) was added Sulfuric acid (2.2 mL, 42mmole, 4.78 eq) at 0° C. while stirring. The reaction mixture wasrefluxed at 90° C. for 1 hour 20 minutes. Crude was quenched with water,neutralized with saturated sodium hydroxide solution until pH 8,extracted with ethyl acetate, and then concentrated in vacuo to givetitle compound as a solid (2.6 g, 99%). Exact mass calculated forC₁₂H₁₄BrN₃O 295.0. found 296.1 (M+H⁷⁹Br, 100), 298.2 (M+H⁸¹Br, 98).

Step 1.50b: Preparation ofN-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide

A mixture of 4-(2-Bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine(1.012 g, 3.417 mmole), 3-methoxy-benzoyl chloride (700 mg, 1.2 eq), andtriethylamine (1.0 mL, 2 eq) in 5 mL THF was stirred at room temperaturefor 10 minutes. The mixture was purified by HPLC to give title compoundas white solid (957 mg, 52%). Exact mass calculated for C₂₀H₂₀BrN₃O₃429.1. found 430.3 (M+H⁷⁹Br, 100), 432.5 (M+H⁸¹Br, 98).

Step 1.50c: Preparation ofN-[4-[2-(4-acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide

A mixture ofN-[4-(2-Bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(90 mg, 0.21 mmole), and 1-piperazin-1-yl-ethanone (32 mg, 1.2 eq), andK₂CO₃ (116 mg, 4.0 eq) in 2 mL DMF was stirred at 120° C. for 20 minutesin microwave. The mixture was purified by HPLC to give title compound asa white solid as TFA salt (97 mg, 97%). ¹H NMR (Acetone-d₆, 400 MHz) δ2.07 (s, 3H), 3.30 (sb, 4H), 3.71 (t, J=4.80 Hz, 2H), 3.75 (s, 3H), 3.79(sb, 2H), 3.87 (s, 3H), 4.60 (t, J=4.80 Hz, 2H), 4.99 (sb, 2H), 6.32 (s,1H), 7.13 (d, J=8.08 Hz, 1H), 7.23 (d, J=9.09 Hz, 1H), 7.42 (t, J=8.08Hz, 1H), 7.53 (m, 2H), 7.56 (d, J=7.83 Hz, 1H), 7.82 (s, 1H), 7.94 (dd,J=8.84, 2.53 Hz, 1H), 9.56 (s, NH). Exact mass calculated forC₂₆H₃₁N₅O₄477.2. found 478.3 (MH⁺).

Example 1.51 Preparation ofN-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-phenyl-acetamide)(Compound 762)

A solution of HATU (57.0 mg, 0.150 mmol), triethylamine (41.8 μl, 0.300mmol) and phenylacetic acid (20.4 mg, 0.150 mmol) in DMF (0.3 mL) wasstirred at room temperature. After 15 min,3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-aniline (30.2mg, 0.100 mmol) was added, and the mixture was stirred at roomtemperature overnight. The solution was diluted with dichloromethane andwashed with saturated sodium bicarbonate. The organic layer was driedwith sodium sulfate, filtered, and evaporated to dryness. The crudeproduct was purified by RP-HPLC and lyophilized to give a TFA-salt as ayellow oil (49 mg, 92%). LCMS m/z (%)=421.3 (M+H 100). ¹H NMR (500 MHz,MeOH-d₄) δ 2.96-3.26 (m, 4H) 3.51-3.55 (m, 2H) 3.55-3.97 (m, 4H) 3.67(s, 2H) 3.70 (s, 3H) 4.36-4.41 (m, 2H) 6.32 (d, J=1.89 Hz, 1H) 7.14 (d,J=8.83 Hz, 1H) 7.21-7.26 (m, 1H) 7.29-7.36 (m, 4H) 7.53 (d, J=1.89 Hz,1H) 7.56 (d, J=2.52 Hz, 1H) 7.66 (dd, J=8.83, 2.52 Hz, 1H).

Example 1.52 Preparation of2-(3-fluoro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide(Compound 766)

A solution of HATU (57.0 mg, 0.150 mmol), triethylamine (41.8 μl, 0.300mmol) and 3-fluorophenylacetic acid (23.1 mg, 0.150 mmol) in DMF (0.3mL) was stirred at room temperature. After 15 min,3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-aniline (30.2mg, 0.100 mmol) was added, and the mixture was stirred at roomtemperature overnight. The solution was diluted with dichloromethane andwashed with saturated sodium bicarbonate. The organic layer was driedwith sodium sulfate, filtered, and evaporated to dryness. The crudeproduct was purified by RP-HPLC and lyophilized to give a TFA-salt as ayellow oil (39 mg, 71%). LCMS m/z (%)=439.5 (M+H 100). ¹H NMR (500 MHz,MeOH-d₄) δ 2.92-3.28 (m, 2H), 3.50-3.57 (m, 2H), 3.59-3.95 (m, 2H), 3.69(s, 2H), 3.71 (s, 3H), 4.37-4.43 (m, 2H), 6.32 (d, J=2.21 Hz, 1H),6.96-7.02 (m, 1H), 7.07-7.13 (m, 1H), 7.13-7.18 (m, 2H), 7.29-7.36 (m,1H), 7.52 (d, J=1.89 Hz, 1H), 7.56 (d, J=2.84 Hz, 1H), 7.67 (dd, J=8.99,2.68 Hz, 1H).

Example 1.53 Preparation of2-(3-chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide(Compound 767)

A solution of HATU (57.0 mg, 0.150 mmol), triethylamine (41.8 μl, 0.300mmol) and 3-chlorophenylacetic acid (25.6 mg, 0.150 mmol) in DMF (0.3mL) was stirred at room temperature. After 15 min,3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-aniline (30.2mg, 0.100 mmol) was added, and the mixture was stirred at roomtemperature overnight. The solution was diluted with dichloromethane andwashed with saturated sodium bicarbonate. The organic layer was driedwith sodium sulfate, filtered, and evaporated to dryness. The crudeproduct was purified by RP-HPLC and lyophilized to give a TFA-salt as ayellow oil (33 mg, 58%). LCMS m/z (%)=455.3 (M+H 100). ¹H NMR (500 MHz,MeOH-d₄) δ 2.95-3.28 (m, 2H), 3.50-3.56 (m, 2H), 3.57-4.05 (m, 2H), 3.68(s, 2H), 3.71 (s, 3H), 4.37-4.42 (m, 2H), 6.32 (d, J=1.89 Hz, 1H), 7.15(d, J=8.83 Hz, 1H), 7.24-7.33 (m, 3H), 7.37-7.39 (m, 1H), 7.52 (d,J=1.89 Hz, 1H), 7.56 (d, J=2.84 Hz, 1H), 7.67 (dd, J=8.99, 2.68 Hz, 2H).

Example 1.54 Preparation ofN-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-acetamide(Compound 768)

A solution of HATU (57.0 mg, 0.150 mmol), triethylamine (41.8 μl, 0.300mmol) and 3-trifluoromethyl phenylacetic acid (30.6 mg, 0.150 mmol) inDMF (0.3 mL) was stirred at room temperature. After 15 min,3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-aniline (30.2mg, 0.100 mmol) was added, and the mixture was stirred at roomtemperature overnight. The solution was diluted with dichloromethane andwashed with saturated sodium bicarbonate. The organic layer was driedwith sodium sulfate, filtered, and evaporated to dryness. The crudeproduct was purified by RP-HPLC and lyophilized to give a TFA-salt as ayellow oil (36 mg, 60%). LCMS m/z (%)=489.3 (M+H 100). ¹H NMR (500 MHz,MeOH-d₄) δ 2.96-3.27 (m, 2H), 3.51-3.56 (m, 2H), 3.58-3.98 (m, 2H), 3.71(s, 2H), 3.78 (s, 3H), 4.37-4.43 (m, 2H), 6.32 (d, J=1.89 Hz, 1H), 7.16(d, J=9.14 Hz, 1H), 7.49-7.59 (m, 4H), 7.61 (d, J=7.57 Hz, 1H),7.65-7.70 (m, 2H).

Example 1.55 Preparation of2-(3-methoxy-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide(Compound 769)

A solution of HATU (57.0 mg, 0.150 mmol), triethylamine (41.8 μl, 0.300mmol) and 3-methoxy-phenylacetic acid (24.9 mg, 0.150 mmol) in DMF (0.3mL) was stirred at room temperature. After 15 min,3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-aniline (30.2mg, 0.100 mmol) was added, and the mixture was stirred at roomtemperature overnight. The solution was diluted with dichloromethane andwashed with saturated sodium bicarbonate. The organic layer was driedwith sodium sulfate, filtered, and evaporated to dryness. The crudeproduct was purified by RP-HPLC and lyophilized to give a TFA-salt as ayellow oil (57 mg, 80%). LCMS m/z (%)=451.2 (M+H 100). ¹H NMR (500 MHz,MeOH-d₄) δ 2.91-3.27 (m, 4H), 3.50-3.55 (m, 2H), 3.57-3.99 (m, 4H), 3.64(s, 2H), 3.70 (s, 3H), 3.77 (s, 3H), 4.35-4.42 (m, 2H), 6.31 (d, J=1.89Hz, 1H), 6.79-6.85 (m, 1H), 6.89-6.95 (m, 2H), 7.14 (d, J=8.83 Hz, 1H),7.22 (t, J=8.20 Hz, 1H), 7.52 (d, J=1.89 Hz, 1H), 7.56 (d, J=2.84 Hz,1H), 7.67 (dd, J=8.98, 2.68 Hz, 1H).

Example 1.56 Preparation ofN-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-m-tolyl-acetamide(Compound 770)

A solution of HATU (57.0 mg, 0.150 mmol), triethylamine (41.8 μl, 0.300mmol) and m-tolylacetic acid (22.5 mg, 0.150 mmol) in DMF (0.3 mL) wasstirred at room temperature. After 15 min,3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-aniline (30.2mg, 0.100 mmol) was added, and the mixture was stirred at roomtemperature overnight. The solution was diluted with dichloromethane andwashed with saturated sodium bicarbonate. The organic layer was driedwith sodium sulfate, filtered, and evaporated to dryness. The crudeproduct was purified by RP-HPLC and lyophilized to give a TFA-salt as ayellow oil (49 mg, 89%). LCMS m/z (%)=435.3 (M+H 100). ¹H NMR (500 MHz,MeOH-d₄) δ 2.31 (s, 3H), 2.89-3.27 (m, 2H), 3.47-3.54 (m, 2H), 3.58-4.00(m, 2H), 3.63 (s, 2H), 3.70 (s, 3H), 4.36-4.41 (m, 2H), 6.31 (d, J=1.89Hz, 1H), 7.04-7.08 (m, 1H), 7.10-7.22 (m, 4H), 7.52 (d, J=1.89 Hz, 1H),7.56 (d, J=2.52 Hz, 1H), 7.66 (dd, J=8.83, 2.52 Hz, 1H).

Example 1.57 Preparation ofN-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-p-tolyl-acetamide(Compound 771)

A solution of HATU (57.0 mg, 0.150 mmol), triethylamine (41.8 μl, 0.300mmol) and p-tolylacetic acid (22.5 mg, 0.150 mmol) in DMF (0.3 mL) wasstirred at room temperature. After 15 min,3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-aniline (30.2mg, 0.100 mmol) was added, and the mixture was stirred at roomtemperature overnight. The solution was diluted with dichloromethane andwashed with saturated sodium bicarbonate. The organic layer was driedwith sodium sulfate, filtered, and evaporated to dryness. The crudeproduct was purified by RP-HPLC and lyophilized to give a TFA-salt as ayellow oil (50 mg, 91%). LCMS m/z (%)=435.3 (M+H 100). ¹H NMR (500 MHz,MeOH-d₄) δ 2.31 (s, 3H), 3.01-3.23 (m, 2H), 3.49-4.00 (m, 2H), 3.51-3.57(m, 2H), 3.62 (s, 2H), 3.71 (s, 3H), 4.35-4.42 (m, 2H), 6.31 (d, J=1.89Hz, 1H), 7.12-7.18 (m, 3H), 7.22 (d, J=8.20 Hz, 2H), 7.52 (d, J=1.89 Hz,1H), 7.53 (d, J=2.84 Hz, 1H), 7.69 (dd, J=8.98, 2.68 Hz, 1H).

Example 1.58 Preparation of2-benzo[1,3]dioxol-5-yl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide(Compound 772)

A solution of HATU (57.0 mg, 0.150 mmol), triethylamine (41.8 μl, 0.300mmol) and 3,4-methylenedioxy-phenylacetic acid (27.0 mg, 0.150 mmol) inDMF (0.3 mL) was stirred at room temperature. After 15 min,3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-aniline (30.2mg, 0.100 mmol) was added, and the mixture was stirred at roomtemperature overnight. The solution was diluted with dichloromethane andwashed with saturated sodium bicarbonate. The organic layer was driedwith sodium sulfate, filtered, and evaporated to dryness. The crudeproduct was purified by RP-HPLC and lyophilized to give a TFA-salt as ayellow oil (48 mg, 83%). LCMS m/z (%)=465.4 (M+H 100). ¹H NMR (500 MHz,MeOH-d₄) δ 2.94-3.24 (m, 2H), 3.48-4.05 (m, 2H), 3.51-3.56 (m, 2H), 3.58(s, 2H), 3.71 (s, 3H), 4.35-4.43 (m, 2H), 5.92 (s, 2H), 6.32 (d, J=1.89Hz, 1H), 6.74-6.83 (m, 2H), 6.83-6.87 (m, 1H), 7.16 (d, J=8.83 Hz, 1H),7.52-7.54 (m, 3H), 7.69 (dd, J=8.98, 2.68 Hz, 1H).

Example 1.59 Preparation ofN-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide(Compound 794)

1-Propanephosphonic acid cyclic anhydride (50% in EtOAc, 106 μl, 0.20mmol) was added to3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-aniline (30.2mg, 0.10 mmol), 4-trifluoromethylphenylacetic acid (18 mg, 0.09 mmol),and triethylamine (123 μl, 0.9 mmol) in ethyl acetate (0.1 mL), and themixture was stirred at room temperature. After 1 h, the reaction wasquenched with saturated sodium bicarbonate, and the product wasextracted with ethyl acetate. The organic layer was washed with brine,dried with sodium sulfate, filtered, and evaporated to dryness. Theresidue was dissolved in methanol (0.5 mL), a solution of acetylchloride (13 μl, 0.2 mmol) in methanol added, and the solution wasevaporated to dryness. The residue was redissolved in methanol andevaporated. The residue was dissolved in water and lyophilized to give aHCl-salt as a white solid (17 mg, 36%). LCMS m/z (%)=489.3 (M+H 100). ¹HNMR (500 MHz, MeOH-d₄) δ 3.05-3.14 (m, 2H), 3.21-3.28 (m, 2H), 3.56-3.61(m, 2H), 3.65-3.74 (m, 2H), 3.79 (s, 3H), 3.81 (s, 2H), 3.90-3.98 (m,2H), 4.42-4.49 (m, 2H), 6.47 (d, J=2.21 Hz, 1H), 7.22 (d, J=9.14 Hz,1H), 7.57 (d, J=8.20 Hz, 2H), 7.64 (d, J=2.84 Hz, 1H), 7.66 (d, J=7.88Hz, 2H), 7.70-7.74 (m, 2H).

Example 1.60 Preparation ofN-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-thiophen-2-yl-acetamide(Compound 795)

1-Propanephosphonic acid cyclic anhydride (50% in EtOAc, 106 μl, 0.20mmol) was added to3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-aniline (30.2mg, 0.10 mmol), 2-thienylacetic acid (13 mg, 0.09 mmol), andtriethylamine (123 μl, 0.9 mmol) in ethyl acetate (0.1 mL), and themixture was stirred at room temperature. After 1 h, the reaction wasquenched with saturated sodium bicarbonate, and the product wasextracted with ethyl acetate. The organic layer was washed with brine,dried with sodium sulfate, filtered, and evaporated to dryness. Theresidue was dissolved in methanol (0.5 mL), a solution of acetylchloride (13 μl, 0.2 mmol) in methanol added, and the solution wasevaporated to dryness. The residue was redissolved in methanol andevaporated. The residue was dissolved in water and lyophilized to givegive a HCl-salt as a yellow solid (22 mg, 54%). LCMS m/z (%)=427.2 (M+H100). ¹H NMR (500 MHz, MeOH-d₄) δ 3.06-3.15 (m, 2H), 3.25-3.31 (m, 2H),3.56-3.61 (m, 2H), 3.67-3.75 (m, 2H), 3.82 (s, 3H), 3.92 (s, 2H), 3.95(dd, J=12.61, 2.52 Hz, 2H), 4.45-4.50 (m, 2H), 6.52 (d, J=2.21 Hz, 1H),6.99 (d, J=3.47 Hz, 1H), 7.00 (d, J=3.47 Hz, 1H), 7.01-7.04 (m, 1H),7.24 (d, J=9.14 Hz, 1H), 7.31 (dd, J=5.04, 1.26 Hz, 1H), 7.66 (d, J=2.52Hz, 1H), 7.71 (dd, J=8.99, 2.68 Hz, 1H), 7.80 (d, J=2.21 Hz, 1H).

Example 1.61 Preparation of1-[4-(2-azetidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound 86)

To a solution of4-(2-(azetidin-1-yl)ethoxy)-3-(1-methyl-1H-pyrazol-5-yl)benzenamine(40.1 mg, 0.147 mmol) in CH₂Cl₂ (2 mL) was added 2,4-difluorophenylisocyanate (18 μL, 0.152 mmol) and stirred for two hours. The crudereaction mixture was purified by SiO₂ column chromatography (Eluent:methanol/CH₂Cl₂=1/6) to afford the title compound (50.4 mg, 80%). LCMSm/z (%)=428 (MH⁺, 100), ¹H NMR (400 MHz, DMSO-d₆) δ: 8.96 (bs, 1H), 8.47(bs, 1H), 8.09-7.98 (m, 1H), 7.45-7.39 (m, 2H), 7.36 (d, J=2.71 Hz, 1H),7.34-7.26 (m, 1H), 7.06 (d, J=8.94 Hz, 1H), 7.06-6.98 (m, 1H), 6.23 (d,J=1.85 Hz, 1H), 3.89 (t, J=5.49 Hz, 2H), 3.67 (s, 3H), 2.98 (t, J=6.92Hz, 4H), 2.60 (t, J=5.47 Hz, 2H), 1.86 (quintet, J=6.99 Hz, 2H).

Example 1.62 Preparation of1-{3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea(Compound 267)

To a solution of3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy)benzenamine(39.2 mg, 0.103 mmol) in CH₂Cl₂ (4 mL) was added 4-chlorophenylisocyanate (18.0 mg) and stirred for two hours. The resulting materialwas purified by HPLC. The product was dried in vacuo to afford the titlecompound as a white solid (50.7 mg, 92%). LCMS m/z (%)=534 (M+H⁷⁹Br,74), 536 (M+H⁸¹Br, 100). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.79 (bs, 1H),8.70 (bs, 1H), 7.60 (s, 1H), 7.52 (dd, J=8.95, 2.71 Hz, 1H), 7.47 (d,J=8.94 Hz, 2H), 7.35 (d, J=2.70 Hz, 1H), 7.31 (d, J=8.91 Hz, 2H), 7.09(d, J=9.03 Hz, 1H), 4.02-3.86 (m, 2H), 3.83 (quint, J=5.80 Hz, 1H), 3.66(s, 3H), 3.35-3.29 (m, 1H), 3.27-3.18 (m, 1H), 3.08 (s, 3H), 2.74-2.56(m, 4H).

Example 1.63 Preparation ofN-{3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-3-methyl-butyramide(Compound 326)

To a solution of3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy)benzenamine(40.3 mg, 0.107 mmol) and pyridine (35 μL) in CH₂Cl₂ (2 mL) was addedisovaleryl chloride (15 μL, 0.122) and stirred for two hours. Theresulting material was purified by HPLC. The product was dried in vacuoto afford the title compound as a white solid (36.0 mg, 73%). LCMS m/z(%)=465 (M+H⁷⁹Br, 75), 467 (M+H⁸¹Br, 90). ¹H NMR (400 MHz, DMSO-d₆) δ:10.00 (bs, 1H), 7.69 (dd, J=8.99, 2.65 Hz, 1H), 7.60 (s, 1H), 7.48 (d,J=2.63 Hz, 1H), 7.09 (d, J=9.06 Hz, 1H), 4.03-3.86 (m, 2H), 3.82 (quint,J=5.76 Hz, 1H), 3.65 (s, 3H), 3.35-3.28 (m, 1H), 3.24-3.17 (m, 1H), 3.08(s, 3H), 2.73-2.55 (m, 4H), 2.16 (d, J=6.96 Hz, 2H), 2.12-2.00 (m, 1H),0.92 (d, J=6.55 Hz, 6H).

Example 1.64 Preparation ofbenzooxazol-2-yl-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-amine(Compound 199)

To a mixture of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenylamine(0.034 g, 0.09 mmol) and 2-chlorobenzoxazole (0.016 g, 0.11 mmol) inisopropanol (1 mL), DIEA (0.031 mL, 0.18 mmol)) was added. The reactionmixture was heated at 60° C. for 4 days, concentrated then subjected toa purification by prep HPLC. The corresponding fractions were collectedand lyophilized to afford Compound 199 (TFA salt) as an off-white solidin 18.4% yield. LCMS m/z (%)=496 (M+H⁷⁹Br, 90), 498 (M+H⁸¹Br, 100). ¹HNMR (400 MHz, Acetone-d₆) δ: 11.80 (bs, 1H), 8.04 (dd, J=2.8, 9.0 Hz,1H), 7.91 (d, J=2.8 Hz, 1H), 7.61 (s, 1H), 7.48-7.42 (m, 2H), 7.36 (d,J=9.0 Hz, 1H), 7.27 (dt, J=1.0, 7.6 Hz, 1H), 7.18 (dt, J=1.2, 7.8 Hz,1H), 4.72-4.63 (m, 1H), 4.60-4.5 (m, 1H), 3.80 (s, 3H), 3.81-3.42 (m, 4Hand water), 2.95-2.82 (m, 2H), 1.95-1.80 (m, 4H), 1.55-1.30 9 (m, 2H).

Example 1.65 Preparation of 5-chloro-thiophene-2-carboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide(Compound 333)

To a mixture of3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine(0.100 g, 0.3 mmol), 5-chlorothiophene-2-carboxylic acid (0.049 g, 0.3mmol), and HATU (0.114 g, 0.3 mmol) in DMF (4 mL), DIEA (0.157 mL, 0.9mmol) was added, then the reaction mixture stirred at room temperatureovernight. The crude product was purified by prep HPLC. Thecorresponding fractions were collected and lyophilized to give aTFA-salt of Compound 333 as a brown solid in 15.1% yield. LCMS m/z(%)=481.2 (M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.41 (s, 1H), 9.95(bs, 1H), 7.90-7.87 (m, 2H), 7.66 (s, 1H), 7.63 (d, J=2.6 Hz, 1H),7.31-7.23 (m, 2H), 4.48-4.27 (m, 2H), 3.66 (s, 3H), 3.81-2.87 (m, 10Hand water).

Example 1.66 Preparation of3,4-difluoro-N-[4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 459)

A mixture of4-[2-(2-Methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine(0.031 g, 0.1 mmol), 3,4-difluorobenzoyl chloride (0.015 mL, 0.12 mmol)and triethylamine (0.018 mL, 0.13 mmol)) in methylene chloride (1.5 mL)was stirred at room temperature overnight and concentrated to give acrude product that was subjected to a purification by prep HPLC. Thecorresponding fractions were collected and lyophilized to give aTFA-salt of Compound 459 as a white solid in 88.2% yield. LCMS m/z(%)=455.5 (M+H, 100).

Example 1.67 Preparation ofN-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-4-fluoro-3-methyl-benzamide(Compound 745)

A mixture of3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenylamine(0.040 g, 0.12 mmol), 4-fluoro-3-methylbenzoyl chloride (0.026 g, 0.12mmol) and triethylamine (0.016 mL, 0.13 mmol)) in methylene chloride(1.5 mL) was stirred at room temperature overnight and concentrated togive a crude product that was subjected to a purification by prep HPLC.The corresponding fractions were collected and lyophilized to give aTFA-salt of Compound 745 as a white solid in 57.0% yield. LCMS m/z(%)=457.4 (M+H, 100).

Example 1.68 Preparation of1-(2-fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea(Compound 65)

A solution of3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenylamine(21.0 mg, 0.07 mmol) in methylene chloride (1 mL) was treated with2-fluorophenyl isocyanate (0.074 mmol), then the reaction mixturestirred at room temperature overnight and concentrated to give an oilyresidue that was subjected to a purification by flash chromatography(SiO₂, CH₂Cl₂/MeOH gradient elution) to afford Compound 65 as a whitesolid in 45.1% yield. LCMS m/z (%)=438.4 (M+H, 100). ¹H NMR (400 MHz,DMSO-d₆) δ: 8.52 (bs, 1H), 8.32-8.28 (m, 1H), 8.02 (bs, 1H), 7.57 (dd,J=2.7, 8.9 Hz, 1H), 7.48 (d, J=2.7 Hz, 1H), 7.39 (d, J=1.8 Hz, 1H),7.18-7.06 (m, 3H), 7.00-6.92 (m, 1H), 6.22 (d, J=1.8 Hz, 1H), 4.11-4.08(m, 2H), 3.75 (s, 3H), 2.67-2.60 (m, 2H), 2.42-2.31 (m, 4H), 1.52-1.43(m, 4H), 1.40-1.32 (m, 2H).

Example 1.69 Preparation ofN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-fluoro-benzamide(Compound 455)

A mixture of3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine(0.036 g, 0.1 mmol), 3-fluoro-benzoyl chloride (14.6 μL, 0.12 mmol) andtriethylamine (18.1 μL, 0.13 mmol)) in methylene chloride (2 mL) wasstirred at room temperature overnight and concentrated to give a crudeproduct that was subjected to a purification by prep HPLC. Thecorresponding fractions were collected and lyophilized to give aTFA-salt of Compound 455 as a tan solid in 85.4% yield. LCMS m/z (%)=487(M+H⁷⁹Br, 97), 489 (M+H⁸¹Br, 100). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.42(s, 1H), 9.71 (bs, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.83-7.73 (m, 3H), 7.66(s, 1H), 7.63-7.57 (m, 1H), 7.46 (t, J=8.7 Hz, 1H), 7.30 (d, J=9.1 Hz,1H), 4.45-4.21 (m, 2H), 3.68 (s, 3H), 3.51-3.42 (m, 2H and water),3.43-3.20 (m, 2H), 2.93-2.60 (m, 2H), 1.97-1.68 (m, 4H).

Example 1.70 Preparation of cyclopentanecarboxylic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]amide(Compound 310)

A mixture of3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine(76 mg, 0.2 mmol), cyclopentyl carboxylic acid (27 mg, 0.24 mmol), HATU(99 mg, 0.26 mmol) and triethylamine (0.3 mL) in DMF (2 mL) was heatedin microwave at 100° C. for 30 min. The crude was purified by HPLC togive title compound (20 mg, 21%) as a brown solid as TFA salt. ¹H NMR(CD₃CN, 400 MHz) δ 1.66-1.95 (m, 8H), 2.70-2.80 (m, 1H), 2.85-3.02 (m,2H), 3.13-3.27 (m, 2H), 3.43 (t, 2H), 3.73 (s, 3H), 3.74-3.80 (m, 2H),3.82-3.90 (m, 2H), 4.34-4.48 (m, 2H), 7.13 (d, J=9.09 Hz, 1H), 7.55 (d,J=2.53 Hz, 1H), 7.57 (s, 1H), 7.76 (dd, J=2.78, 9.35 Hz, 1H), 8.38 (s,1H). Exact mass calculated for C₂₂H₂₉ ⁷⁹BrN₄O₃ 476.1. found 477.3(M+H⁷⁹Br, 100), 479.3 (M+H⁸¹Br, 98).

Example 1.71 Preparation ofN-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide(Compound 343)

A mixture of3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine(57 mg, 0.2 mmol), 4-trifluoromethyl-benzoic acid (42 mg, 0.22 mmol),HATU (91 mg, 0.24 mmol) and triethylamine (0.3 mL) in DMF (2 mL) washeated in microwave at 100° C. for 15 min. The crude was purified byHPLC to give the title compound (65 mg, 71%) as a brown solid as TFAsalt. ¹H NMR (DMSO-d₆, 400 MHz) δ 1.73-1.76 (m, 2H), 1.87-1.92 (m, 2H),2.85-2.90 (m, 2H), 3.29-3.32 (m, 2H), 3.53-3.57 (m, 2H), 3.69 (s, 3H),4.32 (t, J=4.80 Hz, 2H), 6.32 (d, J=2.02 Hz, 1H), 7.26 (d, J=8.59 Hz,1H), 7.50 (d, J=1.78 Hz, 1H), 7.75 (d, J=2.53 Hz, 1H), 7.88-7.94 (m,3H), 8.15 (d, J=8.84 Hz, 2H), 9.81 (s, 1H), 10.5 (s, 1H). Exact masscalculated for C₂₄H₂₅F₃N₄O₂ 458.2. found 459.4 (MH⁺).

Example 1.72 Preparation ofN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-((S)-3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenyl]-3-fluoro-benzamide(Compound 475)

A mixture of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-((S)-3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenylamine(76 mg, 0.2 mmol), 3-fluorobenzoyl chloride (32 mg, 0.22 mmol),triethylamine (0.3 mL) in THF (2 mL) was stirred at r.t. for 20 min. Thesolvent was concentrated in vacuo and the crude was purified by HPLC togive the title compound (40 mg, 40%) as a yellow solid as TFA salt. ¹HNMR (DMSO-d₆, 400 MHz) δ 1.98-2.10 (m, 2H), 2.90-3.45 (m, 6H), 3.68 (s,3H), 4.28-4.30 (m, 1H), 4.39-4.42 (m, 1H), 5.28-5.42 (m, 1H), 7.28-7.31(m, 1H), 7.44-7.49 (m, 1H), 7.57-7.63 (m, 1H), 7.67 (d, 1H), 7.73-7.82(m, 3H), 7.94 (dd, 1H), 10.4 (s, 2H). Exact mass calculated forC₂₃H₂₃BrF₂N₄O₂ 504.1. found 505.5/507.5 (MH⁺).

Example 1.73 Preparation of3-chloro-4-fluoro-N-[4-[2-(4-fluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 538)

A mixture of4-[2-(4-fluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine(80 mg, 0.25 mmol), 4-fluoro-3-chlorobenzoyl chloride (48 mg, 0.25mmol), and triethylamine (0.3 mL) in THF (3 mL) was stirred at r.t. for10 min. The solvent was concentrated in vacuo and the crude was purifiedby HPLC to give the title compound (58 mg, 50%) as a white solid as TFAsalt. ¹H NMR (acetone-d₆, 400 MHz) δ 2.02-2.24 (m, 4H), 3.08-3.18 (m,2H), 3.32-3.42 (m, 2H), 3.63 (t, J=4.55 Hz, 2H), 3.80 (s, 3H), 4.59 (t,J=4.55 Hz, 2H), 4.91-5.03 (m, 1H), 6.30 (d, J=1.77 Hz, 1H), 7.23 (d,J=8.84 Hz, 1H), 7.43-7.51 (m, 2H), 7.81 (t, J=2.27 Hz, 1H), 7.91-7.97(m, 1H), 8.02-8.08 (m, 1H), 8.18 (dd, J=2.53, 7.33 Hz, 1H), 9.71 (s,1H). Exact mass calculated for C₂₄H₂₅ClF₂N₄O₂ 503.1. found 504.1/506.1(MH⁺).

Example 1.74 Preparation ofN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)-phenyl]-4-fluoro-benzamide(Compound 396) Step 1.74a: Preparation of3-[2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of3-[4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (90 mg, 0.2 mmol), 4-fluorobenzoic acid (34 mg,0.24 mmol), HATU (99 mg, 0.26 mmol) and triethylamine (0.3 mL) in DMF (2mL) was heated in microwave at 100° C. for 15 min. The crude waspurified by HPLC to give3-[2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (36 mg, 32%) as a white solid. MS found, 573.5 and575.5.

Step 1.74b: Preparation ofN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)-phenyl]-4-fluoro-benzamide(Compound 396)

To3-[2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester (36 mg) was added HCl in dioxane (4 M, 1 mL), themixture was stirred at r.t. for a few hours. The solvent wasconcentrated in vacuo to give the title compound (36 mg) as HCl salt. ¹HNMR (DMSO-d₆, 400 MHz) δ 1.42-2.08 (m, 4H), 2.72-3.38 (m, 4H), 3.73 (d,3H), 4.45 (m, 1H), 7.33-7.39 (m, 3H), 7.65 (d, J=2.53 Hz, 1H), 7.74 (t,J=3.03 Hz, 1H), 7.90-7.95 (m, 1H), 8.03-8.07 (m, 2H), 8.85-9.02 (m, 1H),9.15-9.30 (m, 1H), 10.4 (s, 1H). Exact mass calculated for C₂₂H₂₂BrFN₄O₂472.1. found 473.3/475.3 (MH⁺).

Example 1.75 Preparation ofN-[4-[2-(4-acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide(Compound 660)

A mixture ofN-[4-(2-Bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide(105 mg, 0.251 mmol), 1-acetylpiperazine (34 mg, 0.264 mmol) andpotassium carbonate (42 mg, 0.301 mmol) in DMF (3 mL) was heated inmicrowave at 120° C. for 20 min. The mixture was purified by HPLC togive title compound (75 mg, 64%) as a white solid as TFA salt. ¹H NMR(CD₃CN, 400 MHz) δ 2.09 (s, 3H), 3.32-3.38 (m, 6H), 3.48 (t, J=5.05 Hz,4H), 3.79 (s, 3H), 4.43 (t, J=4.55 Hz, 2H), 6.39 (d, J=2.02 Hz, 1H),7.18 (d, J=9.09 Hz, 1H), 7.40 (dt, J=2.78, 8.59 Hz, 1H), 7.57-7.63 (m,2H), 7.70-7.74 (m, 2H), 7.80-7.82 (m, 1H), 7.85 (dd, J=2.78, 9.09 Hz,1H), 8.93 (s, 1H). Exact mass calculated for C₂₅H₂₈FN₅O₃ 465.2. found466.4 (MH⁺).

Example 1.76 Preparation ofN-[4-[2-(4,4-difluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide(Compound 778)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide(104 mg, 0.25 mmol), 4,4-difluoropiperidine hydrochloride (43 mg, 0.275mmol) and potassium carbonate (103 mg, 0.75 mmol) in DMF (2 mL) washeated in microwave at 120° C. for 20 min. The crude was purified byHPLC to give the title compound (20 mg, 18%) as a white solid as TFAsalt. ¹H NMR (DMSO-d₆, 400 MHz) δ 2.10-2.23 (m, 4H), 3.10-3.40 (m, 4H),3.57 (t, 2H), 3.68 (s, 3H), 4.37 (t, 2H), 6.30 (d, 1H), 7.25 (d, 1H),7.45 (dt, 1H), 7.50 (d, 1H), 7.57-7.62 (m, 1H), 7.72 (d, 1H), 7.74-7.82(m, 2H), 7.89 (dd, 1H), 10.3 (s, 1H). Exact mass calculated forC₂₄H₂₅F₃N₄O₂ 458.2. found 459.4 (MH⁺).

Example 1.77 Preparation of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea(Compound 1)

To a solution of1-(3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-3-(4-chlorophenyl)urea(44.3 mg, 0.105 mmol) in THF (5 mL), was added triphenyl phosphine (66.2mg, 0.252 mmol) and 1-(2-hydroxyethyl)pyrrolidine (28.0 mg, 0.243 mmol)followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (50μL, 0.258 mmol). After 1 hour, an LC/MS showed only partial conversionso extra triphenyl phosphine (36.9 mg, 0.141 mmol) and1-(2-hydroxyethyl)pyrrolidine (17 μL, 0.145 mmol) was added followed bydropwise addition of diisopropyl azodicarboxylate (DIAD) (27 μL, 0.139mmol). The reaction mixture was stirred at room temperature for 1 morehour and then concentrated. The resulting material was purified by HPLC.The product was dried in vacuo to afford the title compound as a lightbrown solid (31.3 mg, 57%). LCMS m/z (%)=520 (M+H⁸¹Br, 100), 518(M+H⁷⁹Br, 73), ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (bs, 1H), 8.71 (bs, 1H),7.60 (s, 1H), 7.53 (dd, J=8.98, 2.72 Hz, 1H), 7.47 (d, J=8.95 Hz, 2H),7.35 (d, J=2.71 Hz, 1H), 7.31 (d, J=8.90 Hz, 2H), 7.15 (d, J=9.05 Hz,1H), 4.15-4.07 (m, 1H), 4.06-3.98 (m, 1H), 3.66 (s, 3H), 2.80-2.69 (m,1H), 2.69-2.58 (m, 1H), 2.42-2.31 (m, 4H), 1.66-1.55 (m, 4H).

Example 1.78 Preparation of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound 5)

To a solution of3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine(0.96 g, 2.47 mmol) in 10 mL of DMA was added 2,4-difluoro phenylisocyanate (0.42 g, 2.71 mmol), and the mixture was stirred at ambienttemperature overnight. The reaction mixture was diluted with DMSO andwas purified by RP-HPLC. The fractions containing the product werepooled and evaporated to a small volume. The aqueous solution wasneutralized with 1N NaOH to a pH of 9.0 and the product was extractedwith ethyl acetate (2×, 50 mL). The organic layer was dried with sodiumsulfate, filtered and evaporated to dryness to produce1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-ureaas a colorless solid in 59% yield. LCMS m/z (%)=520 (M+H⁷⁹Br, 100), 522(M+H⁸¹Br, 98). ¹H NMR (400 MHz. DMSO-d₆) δ: 9.03 (bs, 1H), 8.49 (bs,1H), 8.01-8.1 (m, 1H), 7.61 (s, 1H), 7.51 (dd, J=8.96 and 2.73 Hz, 1H),7.35 (d, J=2.72 Hz, 1H), 7.27-7.33 (m, 1H), 7.15 (d, J=9.04 Hz, 1H),7.04-7.09 (m, 1H), 4.01-4.11 (m, 2H), 3.67 (s, 3H), 2.51-2.73 (m, 2H),2.34-2.38 (bs, 4H), 1.59-1.63 (bs, 4H).

Example 1.79 Preparation of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyridin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea(Compound 145)

To a solution of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea(0.1 g, 0.24 mmol), 4-(2-hydroxyethyl)-pyridine (0.0443 g, 0.36 mmol),and triphenylphosphine (0.0944 g, 0.36 mmol) in 10 mL of dry THF wasadded diisopropylazo-dicarboxylate (0.0728 g, 0.36 mmol) at ambienttemperature. The mixture was stirred for 2 hours. Next, additionaltriphenylphosphine (0.0944 g, 0.36 mmol), 4-(2-hydroxyethyl)-pyridine(0.0443 g, 0.36 mmol), and diisopropylazodicarboxylate were added andthe reaction mixture further stirred at room temperature overnight. Thesolvent from the reaction mixture was evaporated and the crude residuewas dissolved in 5.0 mL of DMSO and purified by RP-HPLC. The properfractions were collected and concentrated to ¼ volume. The aqueoussolution was neutralized with 1N NaOH and extracted with ethyl acetate(2×, 59 mL). The organic layer was dried with sodium sulfate, filteredand evaporated to dryness to afford1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyridin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-ureaas a brown solid in 44% yield. LCMS m/z (%)=526 (M+H⁷⁹Br, 100), 528(M+H⁸¹Br, 67). ¹H NMR (DMSO-d₆) δ: 9.33 (bs, 1H), 9.24 (bs, 1H), 8.39(dd, J=4.44 and 1.48 Hz, 2H), 7.63 (d, J=7.28 Hz, 1H), 7.59 (s, 1H),7.56 (dd, J=8.94 and 2.71 Hz, 2H), 7.48 (m, 1H), 7.34 (d, J=2.67, 1H),7.31 (d, J=2.67, 1H), 7.28 (dd, J=6.88 and 4.87 Hz, 2H), 7.14 (d, J=9.05Hz, 1H), 7.09 (d, J=5.93 Hz, 1H), 4.01-4.2 (m, 2H), 3.48 (s, 3H),2.96-2.91 (m, 2H).

Example 1.80 Preparation of1-(2,4-difluoro-phenyl)-3-[4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea(Compound 219)

To a solution of4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine(0.08 g, 0.256 mmol) in 2.0 mL of dichloromethane was added 2,4-difluorophenyl isocyanate (0.042 g, 0.280 mmol), and the mixture was stirred atambient temperature overnight. The DCM was evaporated from the reactionmixture, the crude residue was dissolved in 5.0 mL of DMSO and purifiedby RP-HPLC. The proper fractions were collected and lyophilized toafford the1-(2,4-difluoro-phenyl)-3-[4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-ureaas an off-white solid in 75% yield. LCMS m/z (%)=439 (M+H). ¹H NMR (400MHz, Acetone-d₆) δ: 8.46 (bs, 1H), 7.96-8.02 (m, 1H), 7.48 (dd, J=8.9and 2.72 Hz, 1H), 7.39-7.41 (m, 2H), 7.31 (d, J=1.81 Hz, 1H), 7.17 (t,J=1.42 Hz, 1H), 6.94 (d, J=8.94 Hz, 1H), 6.7-6.8 (m, 2H), 6.01 (d,J=1.78 Hz, 1H), 4.62 (t, J=4.74 Hz, 2H), 4.33 (t, J=5.07 Hz, 2H), 3.48(s, 3H).

Example 1.81 Preparation of[4-(2-azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-carbamicacid isopropyl ester (Compound 352)

To a solution of4-(2-azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine(0.06 g, 0.1539 mmol) 2.0 mL of DMA was added isopropyl chloroformate(0.021 g, 0.1687 mmol), and the mixture was stirred at ambienttemperature overnight. The reaction mixture was diluted to 5.0 mL withDMSO and purified by RP-HPLC. The proper fractions were collected andevaporated to ¼ volume and the aqueous was neutralized with 1N NaOH to apH 9.0. Next, the product was extracted with ethyl acetate (2×, 30 mL).The pooled organic layer was dried with sodium sulfate, filtered andevaporated to dryness to afford[4-(2-Azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-carbamicacid isopropyl ester as a colorless solid in 69% yield. LCMS m/z (%)=478(M+H⁷⁹Br, 100), 480 (M+H⁸¹Br, 98). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.79(bs, 1H), 8.69 (bs, 1H), 7.59 (s, 1H), 7.34 (d, J=2.62 Hz, 1H),7.21-7.31 (m, 1H), 7.14 (d, J=9.04 Hz, 1H), 4.02-4.12 (m, 1H), 3.92-4.12(m, 2H), 3.67 (s, 3H), 2.69-2.78 (m, 2H), 2.53-2.59 (m, 2H), 1.4-1.58(bs, 8H), 1.26 (d, J=6.82 Hz, 6H).

Example 1.82 Preparation ofN-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide(Compound 568)

To a solution3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenylamine(0.07 g, 0.2215 mmol) in 2.0 mL of DMA was added DIEA (0.057 g, 0.443mmol), followed by m-trifluoromethyl benzoyl chloride (0.056 g, 0.266mmol), and the reaction mixture was stirred at ambient temperatureovernight. The reaction mixture was diluted to 5.0 mL with DMSO andpurified by RP-HPLC. The proper fractions were collected and lyophilizedto affordN-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamideas an off-white semisolid in 87% yield. LCMS m/z (%)=489 (M+H, 100). ¹HNMR (400 MHz, DMSO-d₆) δ: 10.5 (bs, 1H), 8.29 (s, 1H), 8.26 (d, J=7.94Hz, 1H), 7.98 (d, J=7.83 Hz, 1H), 7.89 (dd, J=8.93 and 2.55 Hz, 1H),7.79 (t, J=7.82 Hz, 1H), 7.72 (d, J=2.53 Hz, 1H), 7.49 (s, 1H), 7.26 (d,J=9.14 Hz, 1H), 6.31 (d, J=1.79 Hz, 1H), 4.29-4.43 (m, 2H), 3.69 (s,3H), 3.55-3.64 (m, 5H), 3.01-3.18 (m, 5H), 1.8-2.1 (m, 2H).

Example 1.83 Preparation ofN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-fluoro-4-trifluoromethyl-benzamide(Compound 606)

To a solution of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenylamine(0.06 g, 0.152 mmol), and N,N-diisopropylethylamine (0.0529 mL, 0.304mmol) in 3.0 mL of DMA was added slowly3-fluoro-4-(trifluoromethyl)benzoyl chloride (0.0278 mL, 0.182 mmol) andthe reaction mixture was stirred at ambient temperature overnight. Thereaction mixture was diluted to 5.0 mL with DMSO and subjected topurification on a RP-HPLC. The proper fractions were collected andlyophilized to furnishN-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-fluoro-4-trifluoromethyl-benzamideas an off-white semisolid in 53% yield. LCMS m/z (%)=585 (M+H⁷⁹Br, 100),587 (M+H⁸¹Br, 98). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.3 (bs, 1H), 8.06 (d,J=11.27 Hz, 1H), 7.95-8.01 (m, 3H), 7.72 (d, J=2.60 Hz, 1H), 7.68 (d,J=2.36 Hz, 1H), 7.31 (d. J=9.48 Hz, 1H), 4.35-4.44 (m, 2H), 3.5-3.9 (m,10H), 2.51-2.69 (m, 5H).

Example 1.84 Preparation of[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-carbamicacid isopropyl ester (Compound 214)

To a solution of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenylamine(0.14 g, 0.443 mmol) in 2.0 mL/1.0 mL DCM/Pyridine mixture was addedisopropyl chloroformate (0.06 g, 0.487 mmol), and the reaction mixturewas stirred at room temperature overnight. The DCM/Pyridine mixture wasevaporated to give a brown residue. The residue was dissolved in 5.0 mLof DMSO and was subjected to purification on RP-HPLC. The properfractions were collected and lyophilized to produce[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-carbamicacid isopropyl ester as a solid in 84% yield. LCMS m/z (%)=405 (M+H,100). ¹H NMR (400 MHz, Acetone-d₆) δ: 8.58 (bs, 1H), 7.66 (dd, J=8.4 and2.6 Hz, 1H), 7.55 (s, 1H), 7.47 (d, J=1.81 Hz, 1H), 7.28 (d, J=1.8 Hz,1H), 7.16 (d, J=8.9 Hz, 1H), 6.05 (d, J=1.86 Hz, 1H), 4.92-4.98, (m,1H), 4.53 (t, J=4.3 Hz, 2H), 3.72 (s, 3H), 3.59 (dd, J=9.63 and 4.86 Hz,2H), 3.28-3.42 (m, 4H), 2.93-2.99 (m, 4H), 1.25 (d, J=6.12 Hz, 6H).

Example 1.85 Preparation of[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-carbamicacid isopropyl ester (Compound 215)

To a solution of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenylamine(0.08 g, 0.253 mmol) in 2.0 mL of DMA was added isopropyl chloroformate(0.034 g, 0.278 mmol), and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was diluted to 5.0 mL withDMSO and was subjected to purification on RP-HPLC. The proper fractionswere collected and lyophilized to afford[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-carbamicacid isopropyl ester as an off-white semisolid in 80% yield. LCMS m/z(%)=403 (M+H, 100). ¹H NMR (400 MH, Acetone-d₆) δ: 8.35 (bs. 1H), 7.45(dd, J=8.4 and 2.6 Hz, 1H), 7.33 (s, 1H), 7.23 (d, J=1.8 Hz, 1H), 6.94(d, J=8.95 Hz, 1H), 6.05 (d, J=1.82 Hz, 1H), 4.69-4.76, (m, 1H), 4.31(t, J=4.36 Hz, 2H), 3.52 (s, 3H), 3.41 (t, J=4.93 Hz, 2H), 3.10-3.30 (m,4H), 2.71-2.80 (m, 4H), 1.05 (d, J=6.12 Hz, 6H).

Example 1.86 Preparation ofN-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide(Compound 527)

To a clear solution of3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine(60.1 g, 178 mmol) in a mixture of n-propanol/ethyl acetate (600/200 mL)at 30-35° C. was added 3-trifluoromethyl benzoyl chloride slowly withstirring. The reaction mixture became turbid initially and solids wereseparated after the mixture was stirred at ambient temperature for 3 to5 hours. The solids were filtered, washed with n-propanol, and dried invacuo at 40° C. overnight to produceN-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamideas a white solid in 72% yield (as the HCl salt). LCMS m/z (%)=509(M+H³⁵Cl, 100), 511 (M+H³⁷Cl, 33) ¹H NMR (400 MHz, DMSO-d₆) δ: 10.7 (bs,1H), 8.39-8.44 (m, 2H), 8.01 (d, J=2.61 Hz, 1H), 7.98 (s, 1H), 7.75-7.83(m, 2H), 7.69 (s, 1H), 7.35 (d, J=9.01, 1H), 4.45-4.65 (m, 2H),3.79-3.89 (m, 4H), 3.69 (s, 3H), 3.36-3.53 (m, 4H with water), 3.05-3.25(m, 2H), 2.99-3.05 (m, 2H).

Example 1.87 Preparation ofN-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)cyclopropanecarboxamide(Compound 271)

To a solution of3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine(0.20 g, 0.60 mmol) in CH₂Cl₂ (14.0 mL) was added cyclopropanecarbonylchloride (0.075 mL, 0.72 mmol) and pyridine (0.061 mL, 0.78 mmol). Thereaction was stirred for 20 min., and concentrated and purified byRP-HPLC. Lyophilization afforded the TFA salt of the title compound as abrown oil (0.027 g, 56%). LCMS m/z (%)=405 (M+H³⁵Cl, 100), 407 (M+H³⁷Cl,38). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.28 (s, 1H), 7.74 (dd, J=2.6, 9.0Hz, 1H), 7.65 (s, 1H), 7.54 (d, J=2.6 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H),4.43-4.37 (m, 1H), 4.32-4.25 (m, 1H), 3.63 (s, 3H), 3.92-2.92 (m, 10H),1.78-1.70 (m, 1H), 0.78 (d, J=6.3 Hz, 4H).

Example 1.88 Preparation of3-methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide(Compound 733)

A mixture of3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine(120 mg, 0.40 mmole), 3-methoxy-benzoyl chloride (81 mg, 0.48 mmole),and triethylamine (0.1 mL, 0.79 mmole) in 5 mL THF was stirred at roomtemperature for 10 minutes. The mixture was purified by HPLC to give thetitle compound as a white solid (TFA salt, 88 mg, 51%). ¹H NMR(Acetone-d₆, 400 MHz) 2.99-3.21 (m, 2H), 3.22-3.45 (m, 2H), 3.66 (t,J=4.80 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.79-3.89 (m, 4H), 4.58 (t,J=4.80 Hz, 2H), 6.29 (d, J=2.02 Hz 1H), 7.13 (dd, J=8.34, 2.53 Hz, 1H),7.22 (d, J=8.84 Hz, 1H), 7.42 (t, J=7.83 Hz, 1H), 7.47 (d, J=1.77 Hz,1H), 7.52 (t, J=1.77 Hz, 1H), 7.56 (d, J=7.07 Hz, 1H), 7.80-7.83 (m,1H), 7.91-7.96 (m, 1H), 9.54 (s, NH). Exact mass calculated forC₂₄H₂₈N₄O₄ 436.2. found 437.5 (MH⁺).

Example 1.89 Analytical Data for Additional Compounds of the PresentInvention

Certain compounds of the present invention were prepared in a similarmanner as described herein. The general synthetic methods and analyticaldata for these compounds are shown in the tables below, the calculatedmass (i.e., Mass Calc) is MH⁺.

Cmpd Mass Mass No. Method Calc Observed 2 B 532.1 534 3 B 534.1 534 &536 4 F 440.2 440 6 B 534.1 534 & 536 7 B 451.1 451 8 F 456.2 456 9 B547.1 549 10 B 518.1 518 & 520 11 B 536.1 536 & 538 12 B 465.1 465 & 46714 B 490.2 490 & 492 15 B 505.2 505 & 507 16 B 492.2 492 & 494 18 B490.1 490 19 B 488.2 487 & 489 20 B 329.2 329 21 F 502.1 502 & 504 22 F518.1 520 23 D 465.1 465 & 467 24 Y 564.1 564 & 566 26 Z 534.1 534 & 53627 F 442.2 442 29 F 436.2 436.2 30 D 367.2 367.3 31 F 514.2 445 32 A, B343.2 343 34 D 401.2 401 36 B 429.2 429 37 D 445.2 445 38 B, Q, F 496.2496.5 39 F 512.2 512.6 40 F 528.2 528.4 41 F 510.2 510.5 42 F 526.2526.3 43 E 453.2 453 45 F 468.2 468 & 470 46 F 438.2 438 47 F 438.2 43848 F 540.2 540 & 542 49 F 524.3 524 50 F 542.2 542 51 F 436.2 436.5 52 M440.2 440 & 442 53 M 424.2 424 54 M 442.2 442 55 M 414.2 414.5 56 M396.2 396.2 57 M 412.1 412.5 58 M 428.2 428.3 59 M 410.2 410.3 60 M426.2 426.3 61 F 558.2 558.3 62 F 556.2 556.3 63 M 458.2 458.3 64 M456.1 456.5 66 F 454.2 454 & 456 67 F 454.2 454 & 456 68 F 420.2 420 69F 498.1 498 & 500 70 F 456.2 456 71 F 450.2 450 72 F 488.2 488 73 F556.2 556 74 F 452.2 452 75 F 450.2 450 76 F 462.2 462 77 F 558.2 558.478 F 556.2 556.2 79 M 458.2 458.3 80 F 434.2 434 81 F 488.2 488 82 M456.1 456.3 83 F 410.2 410 84 F 426.2 426 85 A, B, C, F 440.2 442 88 R483.2 483 & 485 89 E 539.2 540 & 542 90 D 487.3 487 91 D 473.3 473 92 M373.2 373 93 M 439.2 439 94 M 387.2 387 96 R 371.2 371.4 97 F 454.2 45498 J 526.2 526.0 99 J 569.3 568.6 100 J 470.2 569.7 101 F 458.2 458 102F 440.2 440 103 K 498.2 498.3 104 M 469.2 469.5 105 B 379.1 379.4 107 R569.2 568.9 108 E 569.2 568.7 109 K 555.2 555.3 110 K 555.2 555.3 111 J512.2 512.4 112 F 490.2 490 113 D 389.2 389 114 K 498.2 498.5 115 F456.2 456 116 F 440.2 440.6 117 E 455.2 455 118 R 569.2 569.6 119 K555.2 555.1 120 J 470.2 470.5 121 E 478.2 478.4 122 R 457.3 457.5 123 R443.3 443.5 124 R 457.3 457.5 126 G, H, F 528.2 528 127 Y 586.2 486 128B, C, F 469.2 569 129 F 471.2 471 130 F 453.2 453 131 F 483.2 483 132 H,F 474.2 474 133 H, F 472.1 472 & 474 134 R 546.2 546.5 135 E 584.2 584.5136 E 568.3 567.8 137 A, B 476.2 476 138 J 540.2 540.4 139 M 486.2 486140 G, H, F 486.2 486 141 F 484.2 484 142 K 512.2 511.6 143 F 442.2 442& 444 144 R 465.1 467 146 M 532.1 532 & 534 147 D 437.2 437 & 438 148 E584.2 583.6 149 F 444.2 444 150 R 421.2 421.3 152 F 472.2 472 153 F470.2 471 154 D 403.2 403 155 D 417.2 417 156 J 456.2 454.4 157 J 540.2540.4 158 J 555.2 555.4 159 J 484.2 484.6 160 E 439.2 439 161 E 451.2451 162 H, F 470.2 470 163 H, F 470.2 470 164 J 484.2 484.4 165 R 457.2457 166 G 373.2 373 167 J 497.2 496.7 168 R 421.2 420.9 169 R 458.2457.9 170 R 510.1 509.5 171 R 456.2 455.7 172 J 567.2 566.9 173 B 576.2575.4 178 R 458.2 457.2 180 U 435.2 435.4 181 R 470.2 470.3 182 F 486.2486 183 F 468.2 468.6 184 F 484.2 484 185 U 429.2 428.7 186 R 475.1474.9 187 L 581.2 581.2 188 M 455.2 454.8 189 F 468.2 468.6 190 E 483.2483.5 191 K 555.2 555.4 192 F 442.2 442 193 D 417.2 417 194 R 500.3 500195 K 486.3 486 197 L 462.2 462.3 198 I 512.1 512 & 514 200 R 533.2533.5 201 L 490.2 490.4 202 K 519.2 519.4 204 W 486.3 486.4 205 V 428.2428.4 206 W 444.3 444.5 207 K 458.3 458.4 208 R, W 490.2 490.4 210 K567.2 567.5 211 K 526.2 526.2 212 K 513.2 513.5 213 W 449.2 449.3

The general synthetic methods and analytical data for additionalcompounds of the present invention are shown in the table below, thecalculated mass (i.e., Mass Calc) is MH⁺.

Cmpd Mass Mass No. Method Calc Observed 214 D 405.2 405.8 215 D 403.2403.7 216 F 470.2 470.5 217 F 472.2 472.8 218 F 437.1 437.9 219 F 439.2439.8 220 F 506.2 506.3 221 R 387.2 386.8 222 G 345.2 345 223 R 493.2492.7 & 494.7 224 F 456.2 455.7 225 C, P, E, X, J 543.2 543.5 226 C, P,E, X, J 583.2 583.4 227 F 458.2 458.3 228 E 455.2 455.5 229 F 474.2 474230 F 474.2 474 231 F 490.1 490 232 F 456.2 456 233 F 492.2 492 234 F524.1 524 235 F 558.1 558 236 F 470.2 470 237 F 486.2 486 238 W 457.3456.7 239 C, P, E, X, J 586.1 586.3 240 K 443.3 442.9 241 B 421.1 421.2242 B 377.2 377.2 243 D 402.2 402 244 D 416.3 416 245 F 424.2 424.8 246F 424.2 424.5 247 F 436.2 436.8 248 F 440.2 440.7 249 G 359.2 359.2 250F 504.1 504.3 251 F 488.2 488.3 252 F 550.1 550.6 253 F 552.1 552.3 254F 582.0 582.2 255 F 584.1 584.3 256 F 548.1 548.3 257 F 550.1 550.2 258F 492.2 492 259 F 524.2 524 260 F 486.2 486 261 F 498.2 498 262 F 492.2492 263 F 492.2 492 264 F 592.1 592 265 F 506.2 506 266 G 423.1 422.8267 F 534.1 534.2 268 F 536.1 536.2 269 E 533.1 533.3 270 F 518.1 518.4271 E 405.2 404.9 272 E 447.1 447 273 E 459.2 459 274 E 489.1 489 275 J449.1 449.2 & 451.2 276 J 506.2 506.3 & 508.3 277 J 479.2 479.3 & 481.2278 G 409.1 408.7 279 F 520.1 520.4 280 B, Q, R 425.2 425.4 283 B, Q, E491.2 491.3 284 F 522.1 522.2 285 F 504.1 504.3 286 F 504.1 504.3 287 E431.1 431 288 E 459.2 459 289 E 459.2 459 290 F 420.2 420.4 291 F 431.2431.9 292 F 438.2 438.2 293 G 371.2 370.8 294 E 369.2 368.9 295 E 411.2410.8 296 E 395.2 394.8 297 E 423.2 423 298 F 476.1 476.1 299 F 478.1478.3 300 J 546.2 546.4 301 K 532.2 532.2 302 E 423.2 423.3 303 E 423.2423.2 304 F 456.2 456.4 305 AF 447.1 447.1 306 R 463.1 463.4 & 465.4 307R 491.2 491.3 & 493.3 308 E 449.1 448.6 & 450.6 309 R 463.1 462.7 &464.7 310 R 477.1 477.3 & 479.3 311 F 455.2 455.8 312 F 457.2 457.7 313R 491.2 491.3 314 F 472.2 472.2 315 F 484.2 484.4 316 F 484.1 484 317 F490.2 490 318 F 474.2 474 319 F 482.2 481.6 320 F 484.2 484.4 321 F466.3 465.8 322 B 632.2 632.3 323 B 618.1 618.4 324 F 478.3 478.3 325 E481.2 481.3 326 E 465.1 465.3 327 E 427.2 427.2 328 F 505.2 505.5 329 J454.2 454.4 & 456.4 330 J 385.3 385.3 331 F, B 554.2 554.4 332 E 497.2497 333 R 481.1 481.2 334 L 560.1 560.2 335 AG 532.1 532.2 336 E 397.2396.8 337 E 441.2 441.4 338 E 413.2 413.5 339 V 454.2 454.5 340 F 482.2482.5 341 R 519.1 519.4 342 R 509.1 509.4 343 Q, R 459.2 459.4 344 E & M397.2 397 345 E 431.1 431.2 346 F 476.2 476.1 347 E 427.2 427.4 348 E445.1 445.1 349 J 602.3 602.7 350 F 546.1 546.3 351 D 548.1 548.4 352 E479.2 479.4 353 AI 468.2 468.5 354 R 569.1 569.3 355 F 470.2 470.4 356 Y492.1 492.3 357 AG 411.2 411 358 F 472.2 472.4 359 F 454.2 454.5 360 E487.1 487 361 E 517.1 517 362 R 475.2 475.3 363 AG 454.2 454 364 B, Q, R527.2 527.4 365 B, Q, F 496.2 496.3 366 B, Q, R 531.2 531.6 367 E 469.2469.5 368 R 505.2 505.4 369 AG 453.2 453 370 F 470.2 470.5 371 B, Q, R,V 427.1 427.2 372 B, Q, F, V 396.2 396.2 373 B, Q, R, V 431.2 431.3 374T 507.2 507 375 F 472.2 472.4 376 E 469.2 469.5 377 E 473.1 473.2 378 F,M 504.1 504.1 & 506.1 379 Y 476.2 476.4 380 E & M 475.1 475 381 E & M517.1 517 382 AG 489.1 489 383 AG 531.1 531 384 Y 494.1 494.4 385 Y494.1 494.4 386 B, T, Q, R, V 509.1 511.3 387 B, T, Q, R, V 475.0 477.4388 B, T, Q, R, V 459.1 459.2 389 B, T, Q, R, V 477.1 479.3 390 R 459.1459.3 391 B, T, Q, F, V 490.1 492.3 392 B, T, Q, F, V 492.1 494.3 393 F,M 426.2 426.3 & 428.3 394 F, M 488.1 488.4 & 490.4 395 R, M 489.1 489.3& 491.3 396 R, M 473.1 473.3 & 475.3 397 R, M 491.1 491.4 & 493.4 398 R,M 503.1 503.2 & 504.2 399 E 443.2 443.3 400 E 473.2 473.1 401 F 468.2468.4 402 B, Q, R, M 445.2 445.5 403 F 452.2 452.4 404 E 467.2 467.6 405F 466.2 466.2 406 F 450.2 450.4 407 F 470.2 470.4 408 E 441.2 441.4 409E 473.1 473.3 410 E 473.1 473.6 411 E 491.2 491.3 412 E 491.2 491.4 413E 441.2 441.5 414 E 473.2 473.3 415 R 481.2 481.4 416 R 479.2 479.3 417R 545.1 545.1 418 R 543.1 543.6 419 R 533.1 533 420 Q, F, B, V, X, Y502.2 502.3 421 J 458.2 458.3 422 F, M 426.2 426.2 423 E, M 425.2 425.4424 E 441.2 441.3 425 E 473.2 473.6 426 E 473.2 473.6 427 E 465.2 465.4428 F 468.2 468.5 429 F 468.2 468.5 430 E 451.2 451.1 431 E 435.2 435.3432 E 461.2 461.5 433 B, Q, R, M 425.2 425.3 & 427.3 434 B, Q, R, M441.2 441.5 & 443.5 435 P, Q, R 459.2 459.4 436 E 425.2 425.2 437 R529.2 529.2 438 F & M 428.2 428 439 F & M 426.2 426 440 E 509.1 509 441E 477.1 477 442 F 468.2 468.6 443 E 467.2 467.6 444 E & M 413.2 413 445E & M 445.2 445 446 E 487.2 487.7 447 R 531.1 531.3 448 R 547.1 547.3449 E 501.1 501.4 450 E 501.1 501 451 E 485.2 485.4 452 E 551.1 551.5453 E 519.1 519.4 454 E 537.1 537.4 455 E 487.1 487.4 456 E 505.1 505.4457 E 487.2 487.4 458 E 437.2 437.5 459 E 455.2 455.5 460 F 468.2 468.6461 E 531.1 531.5 462 E 565.1 565.3 463 E 504.1 504.4 464 E 498.1 498.4465 E 513.1 513.4 466 E 527.2 527.5 467 E & M 425.2 425 468 P, Q, R427.2 427.4 469 E 459.1 459.3 470 P, Q, R 477.2 477.3 471 P, Q, R 477.2477.2 472 J, Q, E 423.2 423.5 473 J, Q, E 427.2 427.4 474 G, Q, R 505.1505.5 & 507.5 475 G, Q, E 505.1 505.5 & 507.5 476 R 453.2 453.4 477 E493.2 493.4 478 F 490.2 490.5 479 E 441.2 441.4 480 E 475.2 475 481 G,Q, E 491.2 491.4 482 G, Q, E 491.2 491.4 483 E 427.2 427 484 E 443.2 443485 E 477.2 477 486 E 423.2 423 487 E 477.2 477 488 E 423.2 423 489 E425.2 425 490 E 475.1 475.2 491 E 493.2 493.3 492 E 485.2 485.3 493 E457.2 457.3 494 E 491.2 491.5 495 E 437.2 437.5 496 E 437.2 437.5 497 E505.1 505.3 498 E 503.1 503.3 499 E 483.1 483.3 500 E 537.1 537.3 501 E503.1 503.3 502 E 469.1 469.3 503 E 519.1 419.4 504 E 517.1 517.3 505 E497.1 497.5 506 E 551.1 551.5 507 E 517.1 517.3 508 E 483.1 483.3 509 E409.2 409 510 E 405.2 405 511 E 475.2 475 512 E 425.2 425 513 E 409.2409 514 F 484.2 484.3 515 E 503.2 503.2 516 B, T, Q, E 503.1 505.3 517B, T, Q, E 503.1 505.1 518 E 503.2 503.6 519 R 457.2 457.3 520 R 493.1493 521 R 487.2 487 522 R 487.2 487 523 R 503.2 503 524 E 477.1 477 525E 509.1 509 526 E 493.1 493 527 E 509.1 509 528 E 475.1 475 529 E 455.2455 530 E 525.1 525 531 E 471.2 471 532 E 455.2 455 533 P, Q, E 473.2473.2 534 P, Q, R 441.2 441.4 535 P, Q, E 457.2 457.2 536 P, J, Q, E495.2 495.3 537 G, Q, E 455.2 455.4 538 G, Q, E 475.2 475.2 539 P, Q, E459.2 459.2 540 P, Q, E 443.2 443.3 541 R 443.2 443 542 R 470.2 470 543R 475.1 475 544 R 476.1 476 545 P, J, Q, E 479.1 479.2 546 P, J, Q, E459.2 459.3 547 P, Q, E 423.2 423.2 548 B, Q, E 521.1 521.3 & 523.3 549B, Q, E 490.1 490.1 & 492.1 550 R 537.1 537 551 R 503.2 503 552 R 537.1537 553 R 499.2 499 554 R 485.2 485 555 B, Q, E 445.2 445.3 556 B, Q, E429.1 429.1 557 B, Q, E 382.2 382.3 558 E 527.1 527 559 E 473.2 473 560E 527.1 527 561 E 473.2 473 562 E 442.2 442 563 E 442.2 442 564 E 441.2441 565 E 466.2 466 566 E 489.2 489.2 567 E 505.2 505.3 568 E 489.2489.2 569 E 457.2 457.2 570 E 439.2 439.1 571 E 453.2 453.1 572 E 473.2473.6 573 E 527.1 527 574 R 537.2 537 575 P, J, Q, E 475.2 475.2 576 P,J, Q, E 459.2 459.3 577 P, J, T, Q, E 523.1 525.4 578 J, Q, E 457.2457.2 579 P, J, T, Q, E 519.1 521.5 580 P, J, T, Q, E 519.1 519.3 581345.2 345.2 582 E 521.2 521 583 B, T, Q, E 491.1 491.2 584 R 475.2 475.6585 B, T, Q, E 491.1 491.5 586 P, J, Q, R 475.2 475.3 587 B, Q, E 551.2551.3 588 E 563.1 563.2 589 E 563.1 563.3 590 F 502.2 502.6 591 F 502.2502.6 592 B, Q, E, A, E 461.2 461.4 593 B, Q, E, A, E 461.2 461.5 594 B551.2 551.3 595 E 513.1 513.4 596 E 513.1 513.2 597 E 521.2 521.5 598 E471.2 471.5 599 E 543.1 545.3 600 E 503.2 503.4 601 E 529.1 529.2 602 E503.2 503.4 603 E 529.1 529.2 604 E 567.1 567.1 605 E 567.1 567.2 606 E585.1 585.3 607 E 531.1 531.5 608 E 585.1 585.4 609 E 569.1 569.43 610 E569.1 569.43 611 F 518.2 518.5 612 E 587.1 587.4 613 F 518.2 518.5 614 E587.1 587.3 615 P, J, T, Q, R 521.1 521.3 616 P, J, T, Q, R 519.1 521.5617 B, Q, F 532.2 532.4 618 R 441.2 441.3 & 443.3 619 R 455.2 455.3 &457.3 620 E 581.1 581.2 621 E 581.1 581.2 622 P, J, Q, E 488.2 488.2 623P, J, Q, E 468.2 468.3 624 P, J, Q, E 452.2 452.3 625 R 489.2 489.3 626R 489.2 489.3 627 J, Q, E 555.2 555.7 628 J, Q, E 535.2 535.4 629 J, Q,E 519.2 519.6 630 E 483.2 483.4 631 F 498.2 498.5 632 F 482.2 482.4 633E 537.2 537 634 E 537.2 537 635 E 505.2 505 636 E 531.1 531 637 E 531.1531 638 E 531.1 531.1 639 E 563.1 563.2 640 E 521.2 521 641 E 489.2 489642 F 516.2 516 643 F 500.2 500 644 E 565.1 565 645 E 533.1 533 646 F544.2 544 647 P, J, X, Q, E 488.1 488.2 648 F 504.1 504.1 649 F 488.2488.2 650 F 488.2 488.2 651 J, Q, E 546.2 546.6 652 P, J, X, Q, E 472.1472.3 653 J, Q, E 496.2 496.4 654 J, Q, E 527.2 527.6 655 P, J, Q, E538.3 538.5 656 P, J, Q, E 588.3 588.6 657 E 568.3 568.3 658 F 524.2524.3 659 J, Q, E 516.2 516.4 660 E 466.2 466.4 660 E 466.2 466 661 J,Q, E 496.2 496.3 662 P, J, Q, E, V, D 510.2 510.5 663 P, J, Q, E, V, D560.2 560.5 664 F 504.2 504 665 F 504.2 504 666 F 484.2 484 667 E 469.2469 668 E 489.2 489 669 E 489.2 489 670 P, J, T, Q, E 532.1 534.2 671 F468.2 468 672 E 455.2 455 673 E 457.2 457 674 J, T, Q, E 566.1 566.2 &568.2 675 J, T, Q, F 547.1 547.3 & 549.3 676 F 468.2 468 677 J, T, Q, E516.1 516.3 & 518.3 678 X, J, Q, E 536.2 536.3 & 538.3 679 E 473.2 473.2680 E 473.2 473.2 681 E 439.2 439.5 682 E 441.2 441.5 683 E 453.2 453.3684 F 456.2 456.3 685 F 454.2 454.2 686 F 468.2 468.4 687 J, X, Q, E522.1 522.3 & 524.3 688 E 470.2 470 689 E 470.2 470 690 E 450.2 450 691F 451.2 451 692 P, F 550.2 550.6 693 P, F, A, E 460.1 460.2 694 B, C, E585.2 585.5 695 X, J, Q, E 502.1 502.6 & 504.6 696 B, C, E, A, E 495.1495.4 698 F 542.1 542.5 699 J 542.1 542.3 700 F 542.1 542.6 701 F 592.1594.5 702 F 538.2 540.5 703 P, X, J, Q, E 550.2 550.6 704 P, X, J, Q, E500.2 500.7 705 P, X, J, Q, E 516.1 516.3 706 P, J, Q, E 500.2 500.3 707P, J, Q, E 516.2 516.4 708 P, J, Q, E 482.2 482.3 709 Y 592.1 592.3 710Y 592.1 592.3 711 P, J, Q, F 481.2 481.3 712 F 558.1 560.3 713 J 536.2536.4 & 538.4 714 C, P, E, X, J 536.2 536.5 715 C, P, E, X, J 550.2550.4 716 C, P, E, X, J 551.2 551.3 717 B 363.2 363 718 G 622.2 622 719M 522.2 522 720 E 564.2 564 721 F 558.1 558.2 722 F 464.2 464.3 723 C,P, E, X, J 579.2 579.5 724 C, P, E, X, J 550.2 550.4 725 C, P, E, X, J529.1 529.3 726 E 493.2 493 727 B, Q, E 441.2 441.3 728 B 507.2 507 729E 425.2 425 730 B, Q, E 443.2 443.3 731 J, Q, E 484.2 484.3 732 B, Q, E439.2 439.5 733 E 437.2 437 734 Y 560.1 560.3 735 C, P, E, X, J 515.1515.3 736 F 498.2 498.3 737 F 498.2 498.2 738 F 498.2 498.3 739 E 443.2443.5 740 E 443.2 443.5 741 E 443.2 443.5 742 E 455.2 455.3 743 E 439.2439.4 744 E 457.2 457.3 745 E 457.2 457.4 746 F 480.2 480.3 747 P, V, E,J 466.2 466.4 748 P, V, E, J 467.2 467.4 749 F 494.2 494.5 750 E 451.2451.2 751 R 536.2 536.2 752 P, V, E, J 452.2 452.2 753 P, V, E, J 502.2502.1 754 V, E, J 491.2 491.3 755 P, V, E, J 478.2 478.3 756 M 522.1522.4 758 J 532.2 532.4 759 B, Q, E 443.2 443.4 760 B, Q, E 467.2 467.5761 B, Q, E 443.2 443.3 762 R 421.2 421.3 763 R 455.2 455.4 764 R 489.2489.5 765 R 451.2 451.1 766 R 439.2 439.5 767 R 455.2 455.3 768 R 489.2489.3 769 R 451.2 451.2 770 R 435.2 435.3 771 R 435.2 435.3 772 R 465.2465.4 773 R 435.2 435.4 774 J 490.2 490.3 775 G 504.2 504.2 776 G 518.2518.4 777 J 532.1 532.4 778 V, E, J 459.2 459.4 779 E 419.2 419 780 E433.2 433 781 E 447.2 447 782 J 518.2 518.4 783 G 573.2 573.6 784 E461.1 461.3 785 E 439.2 439.5 786 G 485.2 485 787 G 500.2 500 788 G500.2 500 789 V, E, J 503.2 503.6 790 J 476.2 476.2 791 P, V, E, J 479.2479.4 792 R 422.2 422.3 793 R 439.2 439.4 794 R 489.2 489.3 795 R 427.2427.2 796 V, E, J 424.2 424.2 797 L 492.2 492.5 798 L 494.2 494.4 799 R422.2 422.4 800 J, Q, E 502.2 502.2 801 J, Q, E 486.2 486.2 & 488.2 802P, J, Q, E 502.2 502.6 803 P, J, Q, E 486.2 486.4 804 P, J, Q, E 502.2502.3 805 P, J, Q, E, V 438.2 438.4 806 P, J, Q, E, V 488.2 488.3 807 E,M 468.2 468.5 & 470.5 808 AF 509.1 509.1 809 AF 475.1 475.1 810 AF 459.1459.1 811 AF 459.1 459 812 AF 481.2 481.2 813 AF 431.2 431.3 814 AF447.1 447.2 815 AF 431.2 431.3 816 AF 449.1 449.2 817 AF 497.1 497.1 818AF 414.2 414.4 819 AG 546.1 546.4 820 E 475.1 475.1 821 E 487.1 487 822E 517.1 517 823 E 473.1 473.6 824 E 473.2 473.3 825 E 501.1 501 826 E521.2 521 831 B, Q, F 514.2 514.6 832 B, Q, F 512.1 512.4 833 B, Q, F528.2 528.4 834 B, Q, F 510.2 510.5 834 B, Q, F, M 412.1 412.5 836 B, Q,F, M 410.2 410.3

Example 2 Receptor Expression

A. pCMV

Although a variety of expression vectors are available to those in theart, it is preferred that the vector utilized be pCMV. This vector wasdeposited with the American Type Culture Collection (ATCC) on Oct. 13,1998 (10801 University Blvd., Manassas, Va. 20110-2209 USA) under theprovisions of the Budapest Treaty for the International Recognition ofthe Deposit of Microorganisms for the Purpose of Patent Procedure. TheDNA was tested by the ATCC and determined to be viable. The ATCC hasassigned the following deposit number to pCMV: ATCC #203351.

B. Transfection Procedure

For the IP accumulation assay (Example 3), HEK293 cells were transfectedwhile for the DOI binding assay (Example 4) COS7 cells were transfected.Several protocols well known in the art can be used to transfect cells.The following protocol is representative of the transfection proceduresused herein for COS7 or 293 cells.

On day one, COS-7 cells were plated onto 24 well plates, usually 1×10⁵cells/well or 2×10⁵ cells/well, respectively. On day two, the cells weretransfected by first mixing 0.25 ug cDNA in 50 μl serum-free DMEM/welland then 2 μl lipofectamine in 50 μl serum-free DMEM/well. The solutions(“transfection media”) were gently mixed and incubated for 15-30 minutesat room temperature. The cells were washed with 0.5 mL PBS and then 400μl of serum free media was mixed with the transfection media and addedto the cells. The cells were then incubated for 3-4 hours at 37° C./5%CO₂. Then the transfection media was removed and replaced with 1 mL/wellof regular growth media.

For 293 cells, on day one, 13×10⁶ 293 cells per 150 mm plate were platedout. On day two, 2 mL of serum OptimemI (Invitrogen Corporation) wasadded per plate followed by addition of 60 μL of lipofectamine and 16 μgof cDNA. Note that lipofectamine must be added to the OptimemI and mixedwell before addition of cDNA. While complexes between lipofectamine andthe cDNA are forming, media was carefully aspirated and cells weregently rinsed with 5 mL of OptimemI media followed by carefulaspiration. Then 12 mL of OptimemI was added to each plate and 2 mL oftransfection solution was added followed by a 5 hour incubation at 37°C. in a 5% CO₂ incubator. Plates were then carefully aspirated and 25 mLof Complete Media were added to each plate and cells were then incubateduntil used.

Example 3 Inositol Phosphate (IP) Accumulation Assays

A. 5-HT_(2A) Receptor

Compounds of the invention were tested for their ability to activate a5-HT_(2A) receptor clone using an IP accumulation assay. Briefly, HEK293cells were transiently transfected with a pCMV expression vectorcontaining a human 5-HT_(2A) receptor (for the sequence of the receptorsee U.S. Pat. No. 6,541,209, SEQ ID NO:24) as described in Example 2. AnIP accumulation assay was performed as described below. Certaincompounds of the invention had activity values ranging from about 75 μMto about 0.6 nM in this assay.

B. Constitutively Active 5-HT_(2A) Receptor

Compounds of the invention were tested for their ability to inhibit aconstitutively active 5-HT_(2A) receptor clone using an IP accumulationassay. Briefly, 293 cells were transiently transfected with a pCMVexpression vector containing a constitutively active human 5-HT_(2A)receptor (for the sequence of the receptor see U.S. Pat. No. 6,541,209,SEQ ID NO:30) as described in Example 2. The constitutively active human5-HT_(2A) receptor contained the human 5-HT_(2A) receptor described inpart A except that intracellular loop 3 (IC3) and the cytoplamic tailwere replaced by the corresponding human INI 5-HT2C cDNA. An IPaccumulation assay was performed as described below. Certain compoundsof the invention had activity values ranging from about 10 μM to about0.1 nM in this assay.

C. IP Accumulation Assay Protocol

On the day after transfections, media was removed and the cells werewashed with 5 mL PBS followed by careful aspiration. Cells were thentrypsinized with 2 mL of 0.05% trypsin for 20-30 seconds followed byaddition of 10 mL of warmed media, gently titurated to dissociate cells,and an additional 13 mL of warmed media was gently added. Cells werethen counted and 55,000 cells were added to 96-well sterilepoly-D-lysine treated plates. Cells were allowed to attach over a sixhour incubation at 37° C. in a 5% CO₂ incubator. Media was thencarefully aspirated and 100 μL of warm inositol-free media plus 0.5 μCi³H-inositol was added to each well and the plates were incubated for18-20 hours at 37° C. in a 5% CO₂ incubator.

On the next day, media was carefully aspirated and then 0.1 mL of assaymedium was added containing inositol-free/serum free media, 10 μMpargyline, 10 mM lithium chloride, and test compound at indicatedconcentrations. The plates were then incubated for three hours at 37° C.and then wells were carefully aspirated. Then 200 μL of ice-cold 0.1 Mformic acid was added to each well. Plates can then be frozen at thispoint at −80° C. until further processed. Frozen plates were then thawedover the course of one hour, and the contents of the wells(approximately 220 μL) were placed over 400 μL of washed ion-exchangeresin (AG 1-X8) contained in a Multi Screen Filtration plate andincubated for 10 minutes followed by filtration under vacuum pressure.Resin was then washed nine times with 200 μL of water and then tritiatedinositol phosphates (IP, IP2, and IP3) were eluted into a collectingplate by the addition of 200 ul of 1M ammonium formate and an additional10 minute incubation. The elutant was then transferred to 20 mLscintillation vials, 8 mL of SuperMix or Hi-Safe scintillation cocktailswas added, and vials were counted for 0.5-1 minutes in a Wallac 1414scintilation counter.

Example 4 Binding Assays

Compounds of the invention were tested for their ability to bind to a5-HT_(2A) receptor clone membrane preparation using a radioligandbinding assay. Briefly, COS cells were transiently transfected with apCMV expression vector containing a human 5-HT_(2A) receptor (for thesequence of the receptor see U.S. Pat. No. 6,541,209, SEQ ID NO:24) asdescribed in Example 2.

A. Preparation of Crude Membrane Preparations for Radioligand BindingAssays

COS7 cells transfected with recombinant human 5-HT_(2A) receptors werecultured for 48 hr post transfection, collected, washed with ice-coldphosphate buffered saline, pH7.4 (PBS), and then centrifuged at 48,000×gfor 20 min at 4° C. The cell pellet was then resuspended in wash buffercontaining 20 mM HEPES pH 7.4 and 0.1 mM EDTA, homogenized on ice usinga Brinkman polytron, and recentrifuged at 48,000×g for 20 min. at 4° C.The resultant pellet was then resuspended in 20 mM HEPES, pH 7.4,homogenized on ice, and centrifuged (48,000×g for 20 min at 4° C.).Crude membrane pellets were stored at −80° C. until used for radioligandbinding assays.

B. [¹²⁵I]DOI Radioligand Binding Assay

Radioligand binding assays for human 5-HT_(2A) receptor was conductedusing the 5-HT₂ agonist [¹²⁵I]DOI as radioligand. To define nonspecificbinding, 10 μM DOI was used for all assays. For competitive bindingstudies, 0.5 nM [¹²⁵I]DOI was used and compounds were assayed over arange of 0.01 nM to 10 μM. Assays were conducted in a total volume of200 μl in 96-well Perkin Elmer GF/C filter plates in assay buffer (50 mMTris-HCl, pH 7.4, 0.5 mM EDTA, 5 mM MgCl₂, and 10 μM pargyline). Assayincubations were performed for 60 min at room temperature and wereterminated by rapid filtration under vacuum pressure of the reactionmixture over Whatman GF/C glass fiber filters presoaked in 0.5% PEIusing a Brandell cell harvestor. Filters were then washing several timeswith ice-cold wash buffer (50 mM Tris-HCl, pH 7.4). Plates were thendried at room temperature and counted in a Wallac microBetascintillation counter. Certain compounds of the present invention andtheir corresponding activity values are shown in following table.

Compound No. IC₅₀ DOI Binding Assay (nM) 23 1.1 45 10.2 76 5.0 160 13.7Certain other compounds of the invention had activity values rangingfrom about 10 μM to about 0.1 nM in this assay.

Example 5 In Vitro Human Platelet Aggregation Assays

Compounds of the invention were tested for their ability to aggregatehuman platelets. Aggregation assays were performed using a Chrono-LogOptical aggregometer model 410. Human blood (˜100 mL) was collected fromhuman donors into glass Vacutainers containing 3.8% sodium citrate(light blue tops) at room temperature. Platelet rich plasma (PRP) wasisolated via centrifugation at 100 g for 15 min at room temperature.After removal of the aqueous PRP layer, the platelet poor plasma (PPP)was prepared via high speed centrifugation at 2400 g for 20 min.Platelets were counted and their concentration was set to 250,000cells/μl by dilution with PPP. Aggregation assays were conductedaccording to the manufacturer's specifications. Briefly, a suspension of450 μl PRP was stirred in a glass cuvette (1200 rpm) and, after baselinewas established, 1 μM ADP followed by either saline or 1 μM 5HT andcompound of interest (at desired concentrations) were added and theaggregation response recorded. The concentration of ADP used causesapproximately 10-20% of maximal aggregation. The 5-HT concentrationcorresponded to the concentration which produced maximal potentiation.Percent inhibition of aggregation was calculated from the maximumdecrease in optical density of the controls and of the samplescontaining inhibitors. Only the synergistic effect was assessed. Certaincompounds of the invention had activity values ranging from about 80 μMto about 1 nM in this assay. Other compounds of the invention hadactivity values ranging from about 8 μM to about 2 nM in this assay.

Example 6

Efficacy of Compounds of the Invention in the Attenuation of DOI-InducedHypolocomotion in Rats

In this example, compounds of the invention can be tested for inverseagonist activity by determining whether these compounds could attenuateDOI-induced hypolocomotion in rats in a novel environment. DOI is apotent 5-HT_(2a)/_(2C) receptor agonist that crosses the blood-brainbarrier. The standard protocol used is described briefly below.

Animals:

Male Sprague-Dawley rats weighing between 200-300 g are used for alltests. Rats are housed three to four per cage. These rats are naïve toexperimental testing and drug treatment. Rats are handled one to threedays before testing to acclimate them to experimental manipulation. Ratsare fasted overnight prior to testing.

Compounds:

(R)-DOI HCl (C₁₁H₁₆INO₂HCl) can be obtained from Sigma-Aldrich, and isdissolved in 0.9% saline. Compounds of the invention are synthesized atArena Pharmaceuticals Inc. and are dissolved in 100% PEG400. DOI isinjected s.c. in a volume of 1 mL/kg, while compounds of the inventionare administered p.o. in a volume of 2 mL/kg.

Procedure:

The “Motor Monitor” (Hamilton-Kinder, Poway, Calif.) is used for allactivity measurement. This apparatus recorded rears using infraredphotobeams.

Locomotor activity testing is conducted during the light cycle(0630-1830) between 9:00 a.m. and 4:00 p.m. Animals are allowed 30 minacclimation to the testing room before testing began.

In determining the effects of compounds of the invention on DOI-inducedhypoactivity, animals are first injected with vehicle or the compound ofthe invention (50 μmol/kg) in their home cages. Sixty minutes later,saline or DOI (0.3 mg/kg salt) is injected. 10 min after DOIadministration, animals are placed into the activity apparatus andrearing activity is measured for 10 minutes.

Statistics and Results:

Results (total rears over 10 minutes) are analyzed by t-test. P<0.05 isconsidered significant.

Example 7 In vitro Binding of 5-HT_(2A) Receptor Animals:

Animals (Sprague-Dawley rats) are sacrificed and brains are rapidlydissected and frozen in isopentane maintained at −42° C. Horizontalsections are prepared on a cryostat and maintained at −20° C.

LSD Displacement Protocol:

Lysergic acid diethylamide (LSD) is a potent 5-HT_(2A) receptor anddopamine D₂ receptor ligand. An indication of the selectivity ofcompounds for either or both of these receptors involves displacement ofradiolabeled-bound LSD from pre-treated brain sections. For thesestudies, radiolabeled ¹²⁵I-LSD (NEN Life Sciences, Boston, Mass.,Catalogue number NEX-199) can be utilized; spiperone (RBI, Natick, Mass.Catalogue number s-128) a 5-HT_(2A) receptor and dopamine D₂ receptorantagonist, can also utilized. Buffer consists of 50 nanomolar TRIS-HCl,pH 7.4.

Brain sections are incubated in (a) Buffer plus 1 nanomolar ¹²⁵I-LSD;(b) Buffer plus 1 nanomolar ¹²⁵I-LSD and 1 micromolar spiperone; orBuffer plus 1 nanomolar ¹²⁵I-LSD and 1 micromolar Compound of interestfor 30 minutes at room temperature. Sections are then washed 2×10minutes at 4° C. in Buffer, followed by 20 seconds in distilled H₂O.Slides are then air-dried.

After drying, sections are apposed to x-ray film (Kodak Hyperfilm) andexposed for 4 days.

Example 8 Serotonin 5-HT_(2A) Receptor Occupancy Studies in Monkey

In this example, the 5-HT_(2A) receptor occupancy of a compound of theinvention can be measured. The study can be carried out in rhesusmonkeys using PET and ¹⁸F-altanserin.

Radioligand:

The PET radioligand used for the occupancy studies is ¹⁸F-altanserin.Radiosynthesis of ¹⁸F-altanserin is achieved in high specific activitiesand is suitable for radiolabeling 5-HT_(2A) receptors in vivo (seeStaley et al., Nucl. Med. Biol., 28:271-279 (2001) and references citedwithin). Quality control issues (chemical and radiochemical purity,specific activity, stability etc) and appropriate binding of theradioligand are verified in rat brain slices prior to use in PETexperiments.

Drug Doses and Formulations:

Briefly, the radiopharmaceutical is dissolved in sterile 0.9% saline, pHapprox 6-7. The compounds of the invention are dissolved in 60% PEG400-40% sterile saline on the same day of the PET experiment.

Serotonin 5-HT_(2A) occupancy studies in humans have been reported forM100,907 (Grunder et al., Neuropsychopharmacology, 17: 175-185 (1997),and Talvik-Lofti et al., Psychopharmacology, 148:400-403 (2000)). Highoccupancies of the 5-HT_(2A) receptors have been reported for variousoral doses (doses studied ranged from 6 to 20 mg). For example, anoccupancy of >90% was reported for a dose of 20 mg (Talvik-Lofti et al.,supra), which translates to approx. 0.28 mg/kg. It may therefore beanticipated that an i.v. dose of 0.1 to 0.2 mg/kg of M100,907 is likelyto provide high receptor occupancy. A 0.5 mg/kg dose of a Compound ofthe invention can be used in these studies.

PET Experiments:

The monkey is anesthetized by using ketamine (10 mg/kg) and ismaintained using 0.7 to 1.25% isoflurane. Typically, the monkey has twoi.v. lines, one on each arm. One i.v. line is used to administer theradioligand, while the other line is used to draw blood samples forpharmacokinetic data of the radioligand as well as the cold drugs.Generally, rapid blood samples are taken as the radioligand isadministered which then taper out by the end of the scan. A volume ofapproximately 1 mL of blood is taken per time point, which is spun down,and a portion of the plasma is counted for radioactivity in the blood.

An initial control study is carried out in order to measure baselinereceptor densities. PET scans on the monkey are separated by at leasttwo weeks. Unlabeled Compound of the invention is administeredintravenously, dissolved in 80% PEG 400:40% sterile saline.

PET Data Analysis:

PET data are analyzed by using cerebellum as the reference region andusing the distribution volume region (DVR) method. This method has beenapplied for the analysis of ¹⁸F-altanserin PET data in nonhuman primateand human studies (Smith et al., Synapse, 30:380-392 (1998).

Example 9 The Effect of Compounds of the Invention and Zolpidem on DeltaPower in Rats

In this example, the effect of Compounds of the invention on sleep andwakefullness can be compared to the reference drug zolpidem. Drugs areadministered during the middle of the light period (inactivity period).

Briefly, Compounds of the invention are tested for their effects onsleep parameters and are compared to zolpidem (5.0 mg/kg, Sigma, St.Louis, Mo.) and vehicle control (80% Tween 80, Sigma, St. Louis, Mo.). Arepeated measures design is employed in which each rat is to receiveseven separate dosings via oral gavage. The first and seventh dosingsare vehicle and the second through sixth are the test compounds andzolpidem given in counter-balanced order. Since all dosings areadministered while the rats are connected to the recording apparatus,60% CO₂/40% O₂ gas is employed for light sedation during the oral gavageprocess. Rats are fully recovered within 60 seconds following theprocedure. A minimum of three days elapses between dosings. In order totest the effect of the compounds on sleep consolidation, dosing occursduring the middle of the rats' normal inactive period (6 hours followinglights on). Dosing typically occurs between 13:15 and 13:45 using a 24hour notation. All dosing solutions are made fresh on the day of dosing.Following each dosing, animals are continuously recorded until lightsout the following day (˜30 hours).

Animal Recording and Surgical Procedures:

Animals are housed in a temperature controlled recording room under a12/12 light/dark cycle (lights on at 7:00 am) and have food and wateravailable ad libitum. Room temperature (24+2° C.), humidity (50+20%relative humidity) and lighting conditions are monitored continuouslyvia computer. Drugs are administered via oral gavage as described above,with a minimum of three days between dosings. Animals are inspecteddaily in accordance with NIH guidelines.

Eight male Wistar rats (300+25 g; Charles River, Wilmington, Mass.) areprepared with chronic recording implants for continuouselectroencephalograph (EEG) and electromyograph (EMG) recordings. Underisoflurane anesthesia (1-4%), the fur is shaved from the top of theskull and the skin was disinfected with Betadine and alcohol. A dorsalmidline incision is made, the temporalis muscle retracted, and the skullcauterized and thoroughly cleaned with a 2% hydrogen peroxide solution.Stainless steel screws (#000) are implanted into the skull and served asepidural electrodes. EEG electrodes are positioned bilaterally at +2.0mm AP from bregma and 2.0 mm ML and at −6.0 mm AP and 3.0 mm ML.Multi-stranded twisted stainless steel wire electrodes are suturedbilaterally in the neck muscles for recording of the EMG. EMG and EEGelectrodes are soldered to a head plug connector that was affixed to theskull with dental acrylic. Incisions are closed with suture (silk 4-0)and antibiotics administered topically. Pain is relieved by along-lasting analgesic (Buprenorphine) administered intramuscularly oncepost-operatively. Post-surgery, each animal is placed in a clean cageand observed until it is recovered Animals are permitted a minimum ofone week post-operative recovery before study.

For sleep recordings, animals are connected via a cable and acounter-balanced commutator to a Neurodata model 15 data collectionsystem (Grass-Telefactor, West Warwick, R.I.). The animals are allowedan acclimation period of at least 48 hours before the start of theexperiment and are connected to the recording apparatus continuouslythroughout the experimental period except to replace damaged cables. Theamplified EEG and EMG signals are digitized and stored on a computerusing SleepSign software (Kissei Comtec, Irvine Calif.).

Data Analysis:

EEG and EMG data are scored visually in 10 second epochs for waking (W),REMS, NREMS. Scored data are analyzed and expressed as time spent ineach state per half hour. Sleep bout length and number of bouts for eachstate are calculated in hourly bins. A “bout” consists of a minimum oftwo consecutive epochs of a given state. EEG delta power (0.5-3.5 Hz)within NREMS is also analyzed in hourly bins. The EEG spectra duringNREMS are obtained offline with a fast Fourier transform algorithm onall epochs without artifact. The delta power is normalized to theaverage delta power in NREMS between 23:00 and 1:00, a time when deltapower is normally lowest.

Data are analyzed using repeated measures ANOVA. Light phase and darkphase data are analyzed separately. Both the treatment effect withineach rat and the time by treatment effect within each rat is analyzed.Since two comparisons are made, a minimum value of P<0.025 is requiredfor post hoc analysis. When statistical significance is found from theANOVAs, t-tests are performed comparing all compounds to vehicle and thetest compounds to zolpidem.

Example 10 Efficacy of Compounds of the Invention in the Inhibition ofJC Virus Infection of Human Glial Cells

A compound of the invention can be shown to inhibit JC virus infectionof human glial cells using the in vitro model of Elphick et al. [Science(2004) 306: 1380-1383], essentially as described briefly here.

Cells and JC Virus

The human glial cell line SVG (or a suitable subclone thereof, such asSVG-A) is used for these experiments. SVG is a human glial cell lineestablished by transformation of human fetal glial cells by an origindefective SV40 mutant [Major et al., Proc. Natl. Acad. Sci. USA (1985)82: 1257-1261]. SVG cells are cultured in Eagle's minimum essentialmedium (Mediatech Inc., Herndon, Va.) supplemented with 10%heat-inactivated fetal bovine serum, and kept in a humidified 37° C. 5%CO₂ incubator.

The Mad-1/SVEΔ strain of JC virus [Vacante et al., Virology (1989)170:353-361] is used for these experiments. While the host range of JCvirus is typically limited to growth in human fetal glial cells, thehost range of Mad-1/SVEΔ extends to human kidney and monkey cell types.Mad-1/SVEΔ is propagated in HEK cells. Virus titer is measured byhemagglutination of human type O erythrocytes.

Assay for Inhibition of JC Virus Infection

SVG cells growing on coverslips are pre-incubated at 37° C. for 45 minwith or without the compound of the invention diluted in mediacontaining 2% FCS. By way of illustration and not limitation, thecompound of the invention is used at a concentration of about 1 nM toabout 100 μM, at a concentration of about 10 nM to about 100 μM, at aconcentration of about 1 nM to about 10 μM, or at a concentration ofabout 10 nM to about 10 μM.

JC virus (Mad-1/SVEA) is then added at an MOI of 1.0 and the cells areincubated for 1 hr at 37° C. in the continued presence of the compoundof the invention. The cells are then washed 3× in PBS and fed withgrowth media containing the compound of the invention. At 72 hrpost-infection, V antigen positive cells are scored by indirectimmunofluorescence (see below). Controls include the addition of thecompound of the invention at 24 and 48 h post-infection. The percentageof infected cells in untreated cultures is set at 100%.

Indirect Immunofluorescence

For indirect immunofluorescence analysis of V antigen expression, SVGcells growing on coverslips are fixed in ice cold acetone. To detect Vantigen expression, the cells are then incubated for 30 min at 37° C.with a 1:10 dilution of hybridoma supernatant from PAB597. The PAB597hybridoma produces a monoclonal antibody against the SV40 capsid proteinVP1 which has been shown to cross-react with JC virus VP1. The cells arethen washed and incubated with goat anti-mouse Alexa Fluor 488 secondaryantibody for an additional 30 min. After a final wash, the cells arecounterstained with 0.05% Evan's blue, mounted onto glass slides using90% glycerol in PBS and visualized on Nikon E800 epifluorescent scope.Images are captured using a Hamamatsu digital camera and analyzed usingImprovision software.

Example 11 In Vitro Dog Platelet Aggregation Assays

Approximately 50 mL of blood was pooled from 3 male beagles. Theprotocol for analyzing the effects of compounds on platelet aggregationwere identical to those used for human platelets (see Example 5, supra)except 5 μM ADP and 2 μM 5-HT were used to stimulate amplification ofplatelet aggregation. Results: IC₅₀ curves were generated for eachcompound tested which ranged from about 2 nM to greater than about 10μM.

Example 12 Ex-Vivo Dog Whole Blood Aggregation

One hour following PO dosing with a test compound whole blood wascollected from male beagle dogs in a 5 mL vacutainer with exogenousheparin (5 U/mL) added to vacutainer. Aggregation studies were evaluatedby using whole blood Aggregometer (Chronolog Corp.). Briefly, wholeblood (400 uL) was added to saline (600 uL) with constant stirring andactivated with 5 ug of Collagen (Chronolog Corp.). The serotoninresponse was obtained by adding 5-HT (Sigma) to final concentration of2.5 μM. Results: Selected compounds were tested for anti-plateletaggregation activity after single bolus oral dosing. The dose thatafforded maximal inhibition of 5-HT amplified platelet aggregation wasidentified and used for comparison. Certain compounds demonstratedsignificant inhibition of 5-HT amplified collagen platelet aggregationat a range of concentrations from 0.1 mg/kg to 5 mg/kg.

Example 12 Rat In Vivo Thrombosis, Bleeding, Aggregation, PK AssayThrombosis Formation and Bleeding Time:

This model concomitantly measures thrombus formation, bleeding time,platelet aggregation and drug exposure in a single live dosed rat. Testcompounds where administered to male rats (weighing 250-350 g) via POinjection at varying concentrations depending on compound potencyranging from lmpk-100 mpk Animals where then anesthetized using Nembutalapproximately 30 min post PO. Once the animal was fully anesthetizedusing approved surgical techniques the animal's right femoral artery wasisolated in 2 different sections approximately 4-6 mm in length, onearea for probe placement and one for Ferric Chloride patch positioning.The artery was then allowed to stabilize to allow recovery from thesurgery. During stabilization the animal was then intubated and placedon a ventilator (Harvard Apparatus, Inc.) at 75 strokes/min with avolume of 2.5 cubic cm. Following intubation and after stabilization amicro arterial probe (Transonic Systems, Inc) was then placed on thedistal isolated femoral artery. Once the probe was in place the flow wasmonitored using a Powerlab recording system (AD Instruments) to monitorrate of pulsatile flow. A small piece of filter paper soaked in 30%ferric chloride was placed on the area of the artery upstream of theprobe for 10 min. After 5 min of Ferric Choloride patch placement thelast 3 mm of the rat's tail was removed. The tail was then placed in asaline filled glass vial at 37 degree and the time it took for bleedingto stop was recorded. After the Ferric chloride patch was removed theflow was recorded until the artery was occluded and time to occlusionwas recorded.

Whole Blood Aggregation and PK:

Following measurement of bleeding and time to occlusion 5 mL of bloodwas obtained for ex-vivo aggregation analysis by cardiac puncture inheparin (5 U/mL). An additional 500 μL of blood was collected in aseparate vacutainer for PK analysis (plasma drug concentration). Ex-vivoaggregation studies were evaluated by using whole blood Aggregometer(Chronolog Corp.). Briefly, whole blood (400 μL) was added to saline(600 μL) with constant stirring and activated with 2.55 μg of Collagen(Chronolog Corp.). The serotonin response was obtained by adding 5-HT(Sigma) to final concentration of 2.5 μM. Results: Test compounds orreference compounds with acceptable levels of binding to rat 5-HT2Areceptors were evaluated for effects of thrombus formation, bleeding andplatelet activity in a single model. This allowed for the most accuratedemonstration of separation of the test compound effects on plateletmediated thrombus formation from effects on bleeding. For example theED₅₀ generated for Compound 5 for the time to occlusion and bleedingtime in this model demonstrated a ˜7-fold separation (log scale) in thistherapeutic index.

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but are notlimited to, printed publications, and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

1.-27. (canceled)
 28. A method for treating a 5-HT_(2A) mediateddisorder in an individual comprising administering to said individual inneed thereof a therapeutically effective amount of a compound having thestructure

or a pharmaceutically acceptable salt or solvate thereof.
 29. The methodaccording to claim 28, wherein said 5-HT_(2A) mediated disorder isselected from the group consisting of coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, andatrial fibrillation.
 30. A method for treating a condition associatedwith platelet aggregation in an individual comprising administering tosaid individual in need thereof a therapeutically effective amount of acompound having the structure

or a pharmaceutically acceptable salt or solvate thereof.
 31. A methodfor reducing the risk of blood clot formation in an angioplasty orcoronary bypass surgery individual comprising administering to saidindividual in need thereof a therapeutically effective amount of acompound having the structure

or a pharmaceutically acceptable salt or solvate thereof.
 32. A methodfor reducing the risk of blood clot formation in an individual sufferingfrom atrial fibrillation, comprising administering to said individual inneed thereof a therapeutically effective amount of a compound having thestructure

or a pharmaceutically acceptable salt or solvate thereof.
 33. A methodfor treating a sleep disorder in an individual comprising administeringto said individual in need thereof a therapeutically effective amount ofa compound having the structure

or a pharmaceutically acceptable salt or solvate thereof.
 34. The methodaccording to claim 33, wherein said sleep disorder is a dyssomnia. 35.The method according to claim 33, wherein said sleep disorder is aparasomnia.
 36. A method for treating a diabetic-related disorder in anindividual comprising administering to said individual in need thereof atherapeutically effective amount of a compound having the structure

or a pharmaceutically acceptable salt or solvate thereof.
 37. A methodfor treating progressive multifocal leukoencephalopathy in an individualcomprising administering to said individual in need thereof atherapeutically effective amount of a compound having the structure

or a pharmaceutically acceptable salt or solvate thereof.
 38. A methodfor treating hypertension in an individual comprising administering tothe individual in need thereof a therapeutically effective amount of acompound having the structure

or a pharmaceutically acceptable salt or solvate thereof.
 39. A methodfor treating pain in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound having the structure

or a pharmaceutically acceptable salt or solvate thereof. 40.-66.(canceled)
 67. The method according to claim 28, wherein said 5-HT_(2A)mediated disorder is claudication.
 68. The method according to claim 28,wherein said 5-HT_(2A) mediated disorder is peripheral artery disease.69. The method according to claim 28, wherein said 5-HT_(2A) mediateddisorder is vasoconstriction.
 70. The method according to claim 28,wherein said 5-HT_(2A) mediated disorder is vasospasm.
 71. The methodaccording to claim 28, wherein said 5-HT_(2A) mediated disorder isarterial occlusion.
 72. The method according to claim 28, wherein said5-HT_(2A) mediated disorder is thrombosis.
 73. The method according toclaim 28, wherein said 5-HT_(2A) mediated disorder is stroke.